Chemical compounds

ABSTRACT

This invention relates to novel compounds having the formula (I): 
     
       
         
         
             
             
         
       
     
     and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods for the treatment andprevention of cancers and to the use of these pyrazole derivatives inthe manufacture of medicaments for use in the treatment and preventionof cancers.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases (RTK's) are a sub-family of protein kinasesthat play a critical role in cell signalling and are involved in avariety of cancer related processes including cell proliferation,survival, angiogenesis and metastasis. Currently up to 100 differentRTK's including tropomyosin-related kinases (Trk's) have beenidentified.

Trk's are the high affinity receptors activated by a group of solublegrowth factors called neurotrophins (NT). The Trk receptor family hasthree members—TrkA, TrkB and TrkC. Among the NTs there are (i) nervegrowth factor (NGF) which activates TrkA, (ii) brain-derived growthfactor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 whichactivates TrkC. Each Trk receptor contains an extra-cellular domain(ligand binding), a trans-membrane region and an intra-cellular domain(including kinase domain). Upon binding of the ligand, the kinasecatalyzes auto-phosphorylation and triggers downstream signaltransduction pathways.

Trk's are widely expressed in neuronal tissue during its developmentwhere Trk's are critical for the maintenance and survival of thesecells. A post-embryonic role for the Trk/neurotrophin axis (or pathway),however, remains in question. There are reports showing that Trk's playimportant role in both development and function of the nervous system(Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11,272-280).

In the past decade, a considerable number of literature documentationslinking Trk signalling with cancer have published. For example, whileTrk's are expressed at low levels outside the nervous system in theadult, Trk expression is increased in late stage prostate cancers. Bothnormal prostate tissue and androgen-dependent prostate tumours expresslow levels of Trk A and undetectable levels of Trk B and C. However, allisoforms of Trk receptors as well as their cognate ligands areup-regulated in late stage, androgen-independent prostate cancer. Thereis additional evidence that these late stage prostate cancer cellsbecome dependent on the Trk/neurotrophin axis for their survival.Therefore, Trk inhibitors may yield a class of apoptosis-inducing agentsspecific for androgen-independent prostate cancer (Weeraratna, A. T. etal The Prostate, 2000, 45, 140-148).

Furthermore, very recent literature also shows that over-expression,activation, amplification and/or mutation of Trk's are associated withsecretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectalcancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer(Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259).

There are a few reports of selective Trk tyrosine kinase inhibitors.Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research,1999, 59, 2395-2341) and other indolocarbazole analogues (WO0114380) asTrk inhibitors. It was shown that CEP-701 and/or CEP751, when combinedwith surgically or chemically induced androgen ablation, offered betterefficacy compared with mono-therapy alone. GlaxoSmithKline disclosedcertain oxindole compounds as Trk A inhibitors in WO0220479 andWO0220513. Recently, Japan Tobacco reported pyrazolyl condensed cycliccompounds as Trk inhibitors (JP2003231687A).

In addition to the above, Vertex Pharmaceuticals have described pyrazolecompounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789,WO03027111 and WO200437814; and AstraZeneca have reported pyrazolecompounds as inhibitors against IGF-1 receptor kinase (WO0348133).

SUMMARY OF THE INVENTION

In accordance with the present invention, the applicants have herebydiscovered novel pyrazole compounds, or pharmaceutically acceptablesalts thereof, which possess Trk kinase inhibitory activity and areaccordingly useful for their anti-proliferation and/or proapoptotic(such as anti-cancer) activity and in methods of treatment of the humanor animal body. The invention also relates to processes for themanufacture of said pyrazole compounds, or pharmaceutically acceptablesalts thereof, to pharmaceutical compositions containing them and totheir use in the manufacture of medicaments for use in the production ofan anti-proliferation and/or proapoptotic effect in warm-blooded animalssuch as man.

Also in accordance with the present invention the applicants providemethods of using such pyrazole compounds, or pharmaceutically acceptablesalts thereof, in the treatment of cancer.

The properties of the compounds claimed in this invention are expectedto be of value in the treatment of disease states associated with cellproliferation such as cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Furthermore, the compounds, or pharmaceutically acceptable saltsthereof, of the invention are expected to be of value in the treatmentor prophylaxis of cancers selected from congenital fibrosarcoma,mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acutelymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer,myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma,neuroblastoma, Kaposis sarcoma, ovarian cancer, breast cancer includingsecretory breast cancer, colorectal cancer, prostate cancer includinghormone refractory prostate cancer, bladder cancer, melanoma, lungcancer—non small cell lung cancer (NSCLC), and small cell lung cancer(SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma,thyroid cancer including papillary thyroid cancer, mesothelioma andleukaemia; particularly ovarian cancer, breast cancer, colorectalcancer, prostate cancer and lung cancer—NSCLC and SCLC; moreparticularly prostate cancer; and more particularly hormone refractoryprostate cancer.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ and R² independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁸; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁹;

X¹, X² and X³ are independently ═N— or ═CR¹⁰;

R³ and R¹⁰ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R¹¹— or heterocyclyl-R¹²—; whereinR³ and R¹⁰ independently of each other may be optionally substituted oncarbon by one or more R¹³; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁴;

R⁴ is hydrogen or optionally substituted C₁₋₆alkyl; wherein saidoptional substituents are selected from one or more R¹⁵;

R⁵ and R⁶ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁵ and R⁶independently of each other may be optionally substituted on carbon byone or more R¹⁶; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁷;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁸;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH-moiety that nitrogen may be optionally substituted by agroup selected from R¹⁹;

R⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁷ may be optionally substituted on carbon by oneor more R²⁰; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR²¹;

n is 0, 1, 2 or 3; wherein the values of R⁷ may be the same ordifferent;

R⁸, R¹³, R¹⁵, R¹⁶, R¹⁸ and R²⁰ and are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²²— or heterocyclyl-R²³—; whereinR⁸, R¹³, R¹⁵, R¹⁶, R¹⁸ and R²⁰ independently of each other may beoptionally substituted on carbon by one or more R²⁴; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²⁵;

R⁹, R¹⁴, R¹⁷, R¹⁹, R²¹ and R²⁵ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁹, R¹⁴, R¹⁷,R¹⁹, R²¹ and R²⁵ independently of each other may be optionallysubstituted on carbon by on or more R²⁶;

R²⁴ and R²⁶ are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R²⁴ andR²⁶ independently of each other may be optionally substituted on carbonby one or more R²⁷; and wherein if said heterocyclyl contains an—NH-moiety that nitrogen may be optionally substituted by a groupselected from R²⁸;

R¹¹, R¹², R²² and R²³ are independently selected from a direct bond,—O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—, —C(O)N(R³¹)—, —S(O)_(s)—,—SO₂N(R³²)— or —N(R³³)SO₂—; wherein R²⁹, R³⁰, R³¹, R³² and R³³ areindependently selected from hydrogen or C₁₋₆alkyl and s is 0-2;

R²⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

R²⁸ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

Particular values of the variable groups contained in formula (I) are asfollows. Such values may be used, where appropriate, with any of thedefinitions, claims or embodiments defined hereinbefore or hereinafter.

R¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy and carbocyclyl.

R¹ is selected from methyl, isopropoxy and cyclopropyl.

R² is hydrogen.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and carbocyclyl.

R¹ and R² are independently selected from hydrogen, methyl, isopropoxyand cyclopropyl.

X¹ is ═CR¹⁰— and X² and X³ are independently selected from —N═.

X¹ and X² are independently selected from ═CR¹⁰— and X³ is —N═.

X¹ and X³ are independently selected from ═CR¹⁰— and X² is —N═.

X¹, X² and X³ are independently selected from ═CR¹⁰—.

X¹, X² and X³ are selected from —N═.

R³ is selected from hydrogen, cyano, carbamoyl, C₁₋₆alkyl andC₁₋₆alkoxycarbonyl;

wherein R³ may be optionally substituted on carbon by one or more R¹³;

R¹³ is hydroxy.

R³ is selected from hydrogen, cyano, carbamoyl, methyl andmethoxycarbonyl;

wherein R³ may be optionally substituted on carbon by one or more R¹³;

R¹³ is hydroxy.

R³ is selected from hydrogen and C₁₋₆alkyl wherein R³ may be optionallysubstituted on carbon by one or more R¹³; wherein:

R¹³ is hydroxy.

R³ is selected from hydrogen, cyano, carbamoyl, methyl, hydroxymethyland methoxycarbonyl.

R³ is selected from hydrogen, methyl and hydroxymethyl.

R³ and R¹⁰ are independently selected from hydrogen, halo, cyano,carbamoyl, C₁₋₆alkyl and C₁₋₆alkoxycarbonyl; wherein R³ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹³;

R¹³ is selected from hydroxy, amino and C₁₋₆alkanoylamino.

R³ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,cyano, carbamoyl, methyl and ethoxycarbonyl; wherein R³ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹³;

R¹³ is selected from hydroxy, amino and acetylamino.

R³ and R¹⁰ are independently selected from hydrogen, halo, cyano,carbamoyl, C₁₋₆alkyl and C₁₋₆alkoxycarbonyl; wherein R³ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹³; wherein:

R¹³ is hydroxy.

R³ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,cyano, carbamoyl, methyl, aminomethyl, acetylaminomethyl, hydroxymethyland ethoxycarbonyl.

R³ and R¹⁰ are independently selected from hydrogen, fluoro, chloro,cyano, carbamoyl, methyl, hydroxymethyl and ethoxycarbonyl.

R¹⁰ is selected from hydrogen, halo, cyano, carbamoyl and C₁₋₆alkyl;wherein R¹⁰ may be optionally substituted on carbon by one or more R¹³;

R¹³ is selected from amino and C₁₋₆alkanoylamino.

R¹⁰ is selected from hydrogen, fluoro, chloro, cyano, carbamoyl andmethyl; wherein

R¹⁰ may be optionally substituted on carbon by one or more R¹³;

R¹³ is selected from amino and acetylamino.

R¹⁰ is selected from hydrogen, halo, cyano, carbamoyl andC₁₋₆alkoxycarbonyl.

R¹⁰ is selected from hydrogen, fluoro, chloro, cyano, carbamoyl, methyl,aminomethyl and acetylaminomethyl.

R¹⁰ is selected from hydrogen, fluoro, chloro, cyano, carbamoyl andethoxycarbonyl.

R⁴ is hydrogen.

R⁴ is optionally substituted C₁₋₆alkyl; wherein said optionalsubstituents are selected from one or more R¹⁵.

R⁵ and R⁶ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁵ and R⁶ independently of each other may be optionally substituted oncarbon by one or more R¹⁶;

wherein:

R¹⁶ is hydroxy.

R⁵ and R⁶ are independently selected from hydrogen, methyl; ethyl orhydroxymethyl.

R⁵ and R⁶ are independently selected from hydrogen, methyl orhydroxymethyl.

R⁵ is selected from hydrogen, methyl, ethyl or hydroxymethyl.

R⁵ is selected from hydrogen, methyl or hydroxymethyl.

R⁶ is selected from hydrogen or hydroxymethyl.

R⁶ is hydrogen.

A is a direct bond.

A is C₁₋₂alkylene; wherein said C₁₋₂alkylene may be optionallysubstituted by one or more R¹⁸.

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁸; wherein

R¹⁸ is hydroxy.

A is a direct bond or methylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁸; wherein

R¹⁸ is hydroxy.

A is a direct bond, methylene or hydroxymethylene.

Ring C is heterocyclyl; wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁹.

Ring C is carbocyclyl.

Ring C is carbocyclyl or heterocyclyl.

Ring C is phenyl, pyridyl, pyrimidinyl, 1,3-benzodioxolyl or 1H-indolyl.

Ring C is phenyl, pyridyl, 1,3-benzodioxolyl or 1H-indolyl.

Ring C is phenyl, pyrid-2-yl, pyrimidin-2-yl, 1,3-benzodioxol-5-yl or1H-indol-3-yl.

Ring C is phenyl, pyrid-2-yl, 1,3-benzodioxol-5-yl or 1H-indol-3-yl.

Ring C is phenyl.

Ring C is pyridyl.

Ring C is pyrid-2-yl.

Ring C is pyrimidinyl.

Ring C is pyrimidin-2-yl.

R⁷ is selected from halo and C₁₋₆alkyl; wherein R⁷ may be optionallysubstituted on carbon by one or more R²⁰; wherein

R²⁰ is halo.

R⁷ is selected from fluoro and methyl; wherein R⁷ may be optionallysubstituted on carbon by one or more R²⁰; wherein

R²⁰ is fluoro.

R⁷ is halo.

R⁷ is trifluoromethyl and fluoro.

R⁷ is fluoro.

n is 0, 1 or 2; wherein the values of R⁷ may be the same or different.

n is 0 or 1.

n is 1.

Ring C, R⁷ and n together form 4-fluorophenyl, 5-fluoropyrid-2-yl or5-fluoropyrimidin-2-yl.

Ring C, R⁷ and n together form 4-fluorophenyl.

Ring C, R⁷ and n together form 5-fluoropyrid-2-yl.

Ring C, R⁷ and n together form 5-fluoropyrimidin-2-yl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and carbocyclyl;

X¹, X² and X³ are independently ═N— or ═CR¹⁰—;

R³ and R¹⁰ are independently selected from hydrogen, halo, cyano,carbamoyl, C₁₋₆alkyl and C₁₋₆alkoxycarbonyl; wherein R³ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹³;

R⁴ is hydrogen;

R⁵ and R⁶ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁵ and R⁶ independently of each other may be optionally substituted oncarbon by one or more R¹⁶;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁸;

Ring C is carbocyclyl or heterocyclyl;

R⁷ is selected from halo and C₁₋₆alkyl; wherein R⁷ may be optionallysubstituted on carbon by one or more R²⁰;

n is 0, 1 or 2; wherein the values of R⁷ may be the same or different;

R¹³ is selected from hydroxy, amino and C₁₋₆alkanoylamino;

R¹⁶ is hydroxy;

R¹⁸ is hydroxy;

R²⁰ is halo;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and carbocyclyl;

X¹, X² and X³ are independently ═N— or ═CR¹⁰—;

R³ and R¹⁰ are independently selected from hydrogen, halo, cyano,carbamoyl, C₁₋₆alkyl and C₁₋₆alkoxycarbonyl; wherein R³ and R¹⁰independently of each other may be optionally substituted on carbon byone or more R¹³;

R⁴ is hydrogen;

R⁵ and R⁶ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁵ and R⁶ independently of each other may be optionally substituted oncarbon by one or more R¹⁶;

A is a direct bond;

Ring C is carbocyclyl;

R⁷ is halo;

n is 1;

R¹³ is hydroxy; and

R¹⁶ is hydroxy;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is selected from methyl, isopropoxy and cyclopropyl;

R² is hydrogen;

X¹, X² and X³ are independently ═N— or ═CR¹⁰—;

R³ is selected from hydrogen, cyano, carbamoyl, methyl, hydroxymethyland methoxycarbonyl;

R¹⁰ is selected from hydrogen, fluoro, chloro, cyano, carbamoyl, methyl,aminomethyl and acetylaminomethyl;

R⁴ is hydrogen;

R⁵ is selected from hydrogen, methyl, ethyl or hydroxymethyl;

R⁶ is selected from hydrogen or hydroxymethyl;

A is a direct bond, methylene or hydroxymethylene;

Ring C is phenyl, pyrid-2-yl, 1,3-benzodioxol-5-yl or 1H-indol-3-yl;

R⁷ is trifluoromethyl and fluoro;

n is 0, 1 or 2; wherein the values of R⁷ may be the same or different;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is selected from methyl, isopropoxy and cyclopropyl;

R² is hydrogen;

X¹, X² and X³ are independently ═N— or ═CR¹⁰—;

R³ is selected from hydrogen, methyl and hydroxymethyl;

R⁴ is hydrogen;

R⁵ is selected from hydrogen, methyl or hydroxymethyl;

R⁶ is selected from hydrogen or hydroxymethyl;

A is a direct bond;

Ring C is phenyl;

R⁷ is fluoro;

n is 1; and

R¹⁰ is selected from hydrogen, fluoro, chloro, cyano, carbamoyl andethoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable saltthereof.

In a further aspect of the invention there is provided Examples 1, 3, 8,13, 21, 22, 23, 24, 27 or 43 or a pharmaceutically acceptable saltthereof.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the inhibition of Trkactivity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the treatment or prophylaxisof cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment of cancer ina warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment orprophylaxis of cancers (solid tumors and leukemia), fibroproliferativeand differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the production of ananti-proliferative effect.

In an additional embodiment the present invention provides a method ofinhibiting Trk activity comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment of cancer comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancer comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In an additional embodiment the present invention provides a method ofproducing an anti-proliferative effect in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theinhibition of Trk activity.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe inhibition of Trk activity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment of cancer in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment or prophylaxis of cancers (solid tumours andleukaemia), fibroproliferative and differentiative disorders, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe production of an anti-proliferative effect.

In one embodiment where the inhibition of Trk activity is referred toparticularly this refers to the inhibition of Trk A activity.

In another embodiment where the inhibition of Trk activity is referredto particularly this refers to the inhibition of Trk B activity.

Where the treatment (or prophylaxis) of cancer is referred to,particularly it refers to the treatment (or prophylaxis) of congenitalfibrosarcoma, mesoblastic nephroma, mesothelioma, acute myeloblasticleukemia, acute lymphocytic leukemia, multiple myeloma, melanoma,oesophageal cancer, myeloma, hepatocellular, pancreatic, cervicalcancer, Ewings sarcoma, neuroblastoma, Kaposis sarcoma, ovarian cancer,breast cancer including secretory breast cancer, colorectal cancer,prostate cancer including hormone refractory prostate cancer, bladdercancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), andsmall cell lung cancer (SCLC), gastric cancer, head and neck cancer,renal cancer, lymphoma, thyroid cancer including papillary thyroidcancer, mesothelioma, leukaemia, tumours of the central and peripheralnervous system, melanoma, fibrosarcoma including congenital fibrosarcomaand osteosarcoma. More particularly it refers to prostate cancer. Inaddition, more particularly it refers to SCLC, NSCLC, colorectal cancer,ovarian cancer and/or breast cancer. In a further aspect it refers tohormone refractory prostate cancer.

In a further aspect of the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof which process (wherein variable groups are, unlessotherwise specified, as defined in formula (I)) comprises of:

Process a) reaction of a compound of formula (II):

wherein Pg is a nitrogen protecting group; with a compound of formula(III):

wherein L is a displaceable group;Process b) for compounds of formula (I) wherein R⁵ is hydroxymethyl andR⁶ is hydrogen; reaction of a compound of formula (II) with an epoxideof formula (IV):

Process c) for compounds of formula (I) wherein X¹ is ═CR¹⁰—; reacting acompound of formula (V):

with a compound of formula (VI):

Process d) for compounds of formula (I) wherein X¹ is ═N—; reacting acompound of formula (V) with aqueous NaNO₂ solution;Process e) reacting a compound of formula (VII):

wherein L is a displaceable group and Pg is a nitrogen protecting group;with an amine of formula (VIII):

and thereafter if necessary:i) converting a compound of the formula (I) into another compound of theformula (I);ii) removing any protecting groups;iii) forming a pharmaceutically acceptable salt.

L is a displaceable group, suitable values for L are for example, a haloor sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxyor toluene-4-sulphonyloxy group.

Pg is a nitrogen protecting group. Suitable values for Pg are describedherein below.

Specific reaction conditions for the above reactions are as follows.

Process a) Compounds of formula (II) and (III) may be reacted togetherunder standard nucleophilic addition reactions for example in thepresence of a suitable base such as potassium carbonate and a suitablesolvent such as DMF and at a temperature in the range from 25 to 100° C.

Compounds of the formula (II) may be prepared according to Scheme 1:

Compounds of formula (III), (IIa), (IIb) and (IId) are commerciallyavailable compounds, or they are known in the literature, or they areprepared by standard processes known in the art.

Process b) Compounds of formula (II) and (IV) may be reacted togetherunder epoxide ring opening reaction conditions for example in thepresence of a suitable catalyst such as LiClO₄, NaClO₄, Mg(ClO₄)₂ and asuitable solvent such as CH₃CN and at a temperature in the range from 25to 80° C.

Compounds of formula (IV) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process c) Compounds of formula (V) and compounds of formula (VI) may bereacted together in a suitable solvent such as ethanol at refluxtemperature.

Compounds (V) may be prepared according to Scheme 2:

Compounds of formula (Va), (Vb) and (VI) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process d) Compounds of formula (V) and an aqueous NaNO₂ solution may bereacted together in aqueous acetic acid.Process e) Compounds of formula (VII) and (VIII) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (VII) may be prepared according to Scheme 3:

Compounds of the formula (VIII) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

Certain intermediates disclosed herein are novel as such they areprovided as a further feature of the invention.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

DEFINITIONS

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” and “C₁₋₄alkyl” include methyl, ethyl, propyl,isopropyl and t-butyl. However, references to individual alkyl groupssuch as ‘propyl’ are specific for the straight-chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched-chain version only. A similar conventionapplies to other radicals. The term “halo” refers to fluoro, chloro,bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 4-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)—, and a ring sulphur atom may beoptionally oxidised to form the S-oxides. Examples and suitable valuesof the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl,thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino,pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl,imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl,N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone,4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Further examplesand suitable values of the term “heterocyclyl” are morpholino,piperazinyl and pyrrolidinyl. In one aspect of the invention a“heterocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic ring containing 5 or 6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, it may, unless otherwisespecified, be carbon or nitrogen linked, a —CH₂— group can optionally bereplaced by a —C(O)—and a ring sulphur atom may be optionally oxidisedto form the S-oxides.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Particularly “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.

The term “C_(m-n” or “C) _(m-n) group” used alone or as a prefix, refersto any group having m to n carbon atoms.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

An example of “C₁₋₆alkanoyloxy” is acetoxy. Examples of“C₁₋₆alkoxycarbonyl” include C₁₋₄alkoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₆alkoxy”include C₁₋₄alkoxy, C₁₋₃alkoxy, methoxy, ethoxy and propoxy. Examples of“C₁₋₆alkoxyimino” include C₁₋₄alkoxyimino, C₁₋₃alkoxyimino,methoxyimino, ethoxyimino and propoxyimino. Examples of“C₁₋₆alkanoylamino” include formamido, acetamido and propionylamino.Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” includeC₁₋₄alkylsulphonyl, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₆alkylthio”include methylthio and ethylthio. Examples of “C₁₋₆alkylsulphonylamino”include methylsulphonylamino and ethylsulphsulphonylamino. Examples of“C₁₋₆alkanoyl” include C₁₋₄alkanoyl, propionyl and acetyl. Examples of“N—(C₁₋₆alkyl)amino” include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” include di-N-methylamino, di-(N-ethyl)amino andN-ethyl-N-methylamino. Examples of “C₂₋₆alkenyl” are vinyl, allyl and1-propenyl. Examples of “C₂₋₆alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” areN-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl andN-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)carbamoyl” areN—(C₁₋₄alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N—(C₁₋₆alkyl)₂carbamoyl” are N,N—(C₁₋₄alkyl)₂carbamoyl,dimethylaminocarbonyl and methylethylaminocarbonyl.

“RT” or “rt” means room temperature.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

It should be noted that the compounds claimed in this invention arecapable of existing in different resonance structures and thus thecompounds claimed herein include all possible resonance structures, forexample optical isomers, diastereoisomers and geometric isomers and alltautomeric forms of the compounds of the formula (I).

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms.

Formulations

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

An effective amount of a compound of the present invention for use intherapy of cancer is an amount sufficient to symptomatically relieve ina warm-blooded animal, particularly a human the symptoms of cancer, toslow the progression of cancer, or to reduce in patients with symptomsof cancer the risk of getting worse.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substance, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. Examples of such acidaddition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate,camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium, lithium andpotassium salts, alkaline earth metal salts such as aluminum, calciumand magnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; aralkylhalides like benzyl bromide and others. Non-toxicphysiologically-acceptable salts are preferred, although other salts arealso useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

The term composition is intended to include the formulation of theactive component or a pharmaceutically acceptable salt with apharmaceutically acceptable carrier. For example this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition is divided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Combinations

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea);antitumour antibiotics (for example anthracyclines like adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere); and topoisomerase inhibitors (forexample epipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin αvβ3 function and angiostatin);(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy;(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies; and(x) other treatment regimes including: dexamethasone, proteasomeinhibitors (including bortezomib), isotretinoin (13-cis retinoic acid),thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitorsCEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies,targeted radiation therapy with 131I-metaiodobenzylguanidine(131I-MIBG), anti-G(D2) monoclonal antibody therapy with or withoutgranulocyte-macrophage colony-stimulating factor (GM-C SF) followingchemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention, or pharmaceutically acceptable salts thereof, within thedosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

Synthesis

The compounds, or pharmaceutically acceptable salts thereof, of thepresent invention can be prepared in a number of ways well known to oneskilled in the art of organic synthesis. The compounds, orpharmaceutically acceptable salts thereof, of the present invention canbe synthesized using the methods described below, together withsynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as appreciated by those skilled in the art. Suchmethods include, but are not limited to, those described below. Allreferences cited herein are hereby incorporated in their entirety byreference.

The novel compounds, or pharmaceutically acceptable salts thereof, ofthis invention may be prepared using the reactions and techniquesdescribed herein. The reactions are performed in solvents appropriate tothe reagents and materials employed and are suitable for thetransformations being effected. Also, in the description of thesynthetic methods described below, it is to be understood that allproposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents, which are compatible with the reaction conditions,will be readily apparent to one skilled in the art and alternate methodsmust then be used.

EXAMPLES

The invention will now be further described with reference to thefollowing illustrative examples in which, unless stated otherwise:

-   -   (i) temperatures are given in degrees Celsius (° C.); operations        are carried out at room temperature or ambient temperature, that        is, in a range of 18-25° C.;    -   (ii) organic solutions were dried over anhydrous magnesium        sulfate; evaporation of organic solvent was carried out using a        rotary evaporator under reduced pressure (4.5-30 mmHg) with a        bath temperature of up to 60° C.;    -   (iii) chromatography means flash chromatography on silica gel;        thin layer chromatography (TLC) was carried out on silica gel        plates;    -   (iv) in general, the course of reactions was followed by TLC or        liquid chromatography/mass spectroscopy (LC/MS) and reaction        times are given for illustration only;    -   (v) final products have satisfactory proton nuclear magnetic        resonance (NMR) spectra and/or mass spectra data;    -   (vi) yields are given for illustration only and are not        necessarily those which can be obtained by diligent process        development; preparations were repeated if more material was        required;    -   (vii) when given, NMR data is in the form of delta values for        major diagnostic protons, given in part per million (ppm)        relative to tetramethylsilane (TMS) as an internal standard,        determined at 300 MHz in DMSO-d₆ unless otherwise stated;    -   (viii) chemical symbols have their usual meanings;    -   (ix) solvent ratio was given in volume:volume (v/v) terms.    -   (x) the following abbreviations have been used:        -   EtOAc ethyl acetate;        -   EtOH ethanol;        -   THF tetrahydrofuran;        -   DIEA diisopropylethylamine        -   MeOH methanol; and        -   DCM dichloromethane.

Example 1(2R)-2-[9-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-methyl-9H-purin-2-ylamino]-2-(4-fluorophenyl)ethanol

A mixture of(R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methylpyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol(Method 40; 0.3 g, 0.8 mmol) and formamidine acetate (0.2 g, 1.6 mmol)in EtOH (8 ml) was heated to reflux for 12 hours. The reaction was thenconcentrated, dissolved in DCM (50 ml), and washed with saturated NaHCO₃solution (50 ml). The organic layer was then dried, filtered, andconcentrated. The resulting solid was purified by column chromatography(DCM:MeOH=20:1) to give the title compound (0.11 g, 35%). NMR (400 MHz,CD₃OD) 8.32 (s, 1H), 7.46-7.43 (m, 2H), 7.06-7.02 (m, 2H), 6.24 (s, 1H),5.10-5.02 (m, 1H), 3.87-3.75 (m, 2H), 2.61 (s, 3H), 1.99-1.96 (m, 1H),1.10-1.08 (m, 2H), 0.80-0.75 (m, 2H). MS: Calcd.: 393. Found: [M+H]⁺394.

Examples 2-8

Following a similar procedure to Example 1, the following compounds weresynthesized from a suitable amino-pyrimidine by treatment withformamidine acetate (or acetamidine hydrochloride for Example 6).

Ex Compound NMR SM 2 9-(5-Cyclopropyl-1H- 0.77 (m, 2H), 1.02 (m, 2H),1.42 (m, 3H), Method pyrazol-3-yl)-N-[(1S)-1- 1.98 (m, 1H), 5.04 (br s,1H), 6.30 (m, 1H), 7.09 (m, 41 (4-fluorophenyl)ethyl]- 2H), 7.43 (m,2H), 7.85 (br s, 1H), 8.38 (s, 1H), 9H-purin-2-amine 8.68 (s, 1H), 12.73(s, 1H) 3 (2R)-2-{[9-(5- 0.77 (m, 2H), 1.04 (m, 2H), 1.99 (m, 1H),Method Cyclopropyl-1H-pyrazol- 3.63 (m, 2H), 4.91 (m, 1H), 6.20 (m, 1H),7.09 (m, 42 3-yl)-9H-purin-2- 2H), 7.43 (m, 2H), 7.60 (br s, 1H), 8.38(s, 1H), yl]amino}-2-(4- 8.68 (s, 1H), 12.73 (s, 1H)fluorophenyl)ethanol 4 9-(5-Cyclopropyl-1H- 0.71 (m, 2H), 0.99 (m, 2H),1.96 (m, 1H), Method pyrazol-3-yl)-N-(4- 4.50 (m, 2H), 6.34 (m, 1H),7.09 (m, 2H), 7.39 (m, 43 fluorobenzyl)-9H-purin- 2H), 7.88 (br s, 1H),8.39 (s, 1H), 8.70 (s, 1H), 2-amine 12.74 (s, 1H) 5 9-(5-Cyclopropyl-1H-0.75 (m, 2H), 1.02 (m, 2H), 1.42 (m, 3H), Methodpyrazol-3-yl)-N-[(1R)-1- 1.98 (m, 1H), 5.04 (br s, 1H), 6.28 (m, 1H),7.09 (m, 44 (4-fluorophenyl)ethyl]- 2H), 7.44 (m, 2H), 7.85 (br s, 1H),8.37 (s, 1H), 9H-purin-2-amine 8.67 (s, 1H), 12.73 (s, 1H) 69-(5-Cyclopropyl-1H- (CDCl₃): 0.71 (m, 2H), 0.95 (m, 2H), 1.45 (m,Method pyrazol-3-yl)-N-[(1S)-1- 3H), 1.86 (m, 1H), 2.60 (s, 3H), 5.07(m, 1H), 41 (4-fluorophenyl)ethyl]-8- 5.80 (br s, 1H), 6.05 (s, 1H),6.90 (m, 2H), methyl-9H-purin-2- 7.30 (m, 2H), 8.59 (s, 1H), 11.74 (brs, 1H) amine 7 (2R)-2-(4-Fluorophenyl)- (400 MHz) 12.68 (s, 1H), 8.70(s, 1H), 8.40 (s, Method 2-(9-(5-methyl-1H- 1H), 7.61 (b, 1H), 7.46 (m,2H), 7.12 (m, 2H), 45 pyrazol-3-yl)-9H-purin- 6.38 (b, 1H), 4.93 (m,2H), 3.65 (m, 2H), 2-ylamino)ethanol 2.34 (s, 3H). MS: Calcd.: 353;Found: [M + H]⁺ 354. 8 N-((S)-1-(4- (400 MHz) 12.57 (s, 1H), 8.70 (s,1H), 8.39 (s, Method Fluorophenyl)ethyl)-9- 1H), 7.92 (b, 1H), 7.44 (m,2H), 7.09 (m, 2H), 46 (5-isopropoxy-1H- 6.05 (b, 1H), 5.10 (b, 1H), 4.53(m, 1H), pyrazol-3-yl)-9H-purin- 1.46 (d, J = 6.8 Hz, 3H), 1.40 and 1.35(d, J = 6.0 Hz, 2-amine 6H). MS: Calcd.: 381; Found: [M + H]⁺ 382.

Example 9(2R)-2-[3-(5-Cyclopropyl-1H-pyrazol-3-yl)-7-methyl-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-5-ylamino]-2-(4-fluorophenyl)ethanol

To a solution of(R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methylpyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol(Method 40; 0.18 g, 0.47 mmol) in aqueous acetic acid (5%, 3 ml) wasadded dropwise the aqueous solution of NaNO₂ (0.032 g, 0.47 mmol, 1 mlH₂O) at 25° C. The reaction was allowed to stir for an additional 5minutes, treated with water (10 ml), and extracted with DCM (3×25 ml).The organic layer was washed with saturated NaHCO₃ solution (50 ml),dried, filtered, and concentrated. The resulting solid was purified bycolumn chromatography (DCM:MeOH=30:1) to give the title compound (0.15g, 81%). NMR (400 MHz, CD₃OD) 7.46-7.42 (m, 2H), 7.06-7.01 (m, 2H), 6.21(s, 1H), 5.14-5.06 (m, 1H), 3.86-3.79 (m, 2H), 2.74 (s, 3H), 2.03-2.01(m, 1H), 1.11-1.08 (m, 2H), 0.83-0.79 (m, 2H). MS: Calcd.: 394. Found:[M+H]⁺ 395.

Example 103-(5-Cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-5-amine

To a solution of(S)—N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]pyrimidine-2,4,5-triamine(Method 8; 0.04 g, 0.1 mmol) in aqueous acetic acid (5%, 3 ml) wasslowly added an aqueous NaNO₂ solution (0.008 g, 0.1 mmol, 1 ml H₂O).The reaction was allowed to stir for an additional 5 minutes, treatedwith water (10 ml), and extracted with DCM (3×25 ml). The combinedorganic layer was washed with saturated NaHCO₃ solution (50 ml), dried,filtered, and concentrated. The resulting solid was purified by columnchromatography (DCM:MeOH=15:1) to give the title compound (0.015 g,40%). NMR (400 MHz, CD₃OD) 9.05 (s, 1H), 7.44-7.41 (m, 2H), 7.03-6.99(m, 2H), 6.23 (s, 1H), 5.16-5.07 (m, 1H), 2.03-2.00 (m, 1H), 1.55 (d,J=6.8 Hz, 3H), 1.11-1.09 (m, 2H), 0.85-0.80 (m, 2H). MS: Calcd.: 364.Found: [M+H]⁺ 365.

Example 11 Ethyl9-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(S)-1-(4-fluorophenyl)ethylamino]-9H-purine-6-carboxylate

A mixture of (S)-ethyl5-amino-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]pyrimidine-4-carboxylate(Method 47; 0.6 g, 1.4 mmol) and formamidine acetate (0.32 g, 3.1 mmol)in EtOH (20 ml) was heated to reflux for 12 hours. The reaction was thenconcentrated, and the resulting residue was dissolved in EtOAc (50 ml)and washed with saturated NaHCO₃ solution (50 ml). The organic layer wasdried, filtered, and concentrated. The resulting solid was purified bycolumn chromatography (DCM:MeOH=20:1) to give the title compound (0.058g, 8%). NMR (400 MHz, CD₃OD) 8.48 (s, 1H), 7.45-7.41 (m, 2H), 7.03-6.99(m, 2H), 6.25 (s, 1H), 5.12-5.03 (m, 1H), 4.50 (q, J=7.2 Hz, 2H),2.00-1.96 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 1.44 (t, J=7.2 Hz, 3H),1.10-1.08 (m, 2H), 0.81-0.74 (m, 2H). MS: Calcd.: 435. Found: [M+H]⁺436.

Example 12[9-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(S)-1-(4-fluorophenyl)ethylamino]-9H-purin-6-yl]methanol

A solution of ethyl9-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(S)-1-(4-fluorophenyl)ethylamino]-9H-purine-6-carboxylate(Example 11; 0.03 g, 0.069 mmol) in THF (3 ml) was cooled to 0° C. Towhich was slowly added lithium aluminium hydride (1.0 M in THF, 0.076ml, 1.1 eq.). The reaction mixture was stirred at 0° C. for 30 minutes,at which point sodium sulfate decahydrate was added until bubblingstopped. The reaction was then filtered through a plug of celite, washedwith THF (3×30 ml), and concentrated. The resulting residue was purifiedby column chromatography (DCM:MeOH=15:1) to give the title compound(0.09 g, 33%). NMR (400 MHz, CDCl₃) 8.27 (s, 1H), 7.39-7.36 (m, 2H),7.03-6.98 (m, 2H), 6.32 (s, 1H), 5.65-5.64 (m, 1H), 5.10-5.07 (m, 1H),5.03 (s, 2H), 3.87-3.85 (m, 1H), 1.93-1.88 (m, 1H), 1.57 (d, J=6.8 Hz,3H), 1.08-1.06 (m, 2H), 0.81-0.77 (m, 2H). MS: Calcd.: 393. Found:[M+H]⁺ 394.

Example 133-(5-Cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-imidazo[4,5-b]pyridin-5-amine

A mixture of(S)—N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]pyridine-2,3,6-triamine(Method 48; 0.240 g, 0.68 mmol) and formamidine acetate (0.113 g, 1.09mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to25° C., the reaction mixture was treated with saturated NaHCO₃ solution(10 ml) and EtOAc (30 ml). The organic layer was separated, washed withbrine (10 ml), and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:3) to give the title compound as an off-white solid(0.144 g, 58%). NMR (400 MHz) 12.57 (s, 1H), 8.25 (s, 1H), 7.72 (d,J=8.4 Hz, 1H), 7.41 (m, 2H), 7.32 (d, J=6.4 Hz, 1H), 7.10 (m 2H), 6.56(d, J=8.8 Hz, 1H), 6.26 (s, 1H), 4.99 (m, 1H), 1.97 (m, 1H), 1.45 (d,J=6.8 Hz, 3H), 1.04 (m, 2H), 0.78-0.69 (m, 2H). MS: Calcd.: 362. Found:[M+H]⁺ 363.

Examples 14-26

Following a similar procedure to Example 13, the following compoundswere synthesized from a suitable amino-pyridine followed by treatmentwith formamidine acetate.

Ex. Compound NMR/MS SM 14 N-(4-Fluorobenzyl)-3- NMR (400 MHz) 12.59 (s,1H), 8.27 (s, 1H), Method (5-cyclopropyl-1H- 7.74 (d, J = 8.4 Hz, 1H),7.40 (m, 2H), 7.13 (m, 49 pyrazol-3-yl)-3H- 2H), 6.54 (d, J = 8.8 Hz,1H), 6.36 (s, 1H), imidazo[4,5- 4.50 (d, J = 5.6 Hz, 2H), 1.95 (m, 1H),1.00 (m, 2H), b]pyridin-5-amine 0.68 (m, 2H). MS: Calcd.: 348; Found:[M + H]⁺ 349. 15 (2R)-2-[3-(5- (400 MHz) 12.58 (s, 1H), 8.26 (s, 1H),7.72 (d, J = 8.8 Hz, Method Cyclopropyl-1H- 1H), 7.43 (m, 2H), 7.24 (d,J = 6.4 Hz, 50 pyrazol-3-yl)-3H- 1H), 7.09 (m, 2H), 6.62 (d, J = 8.8 Hz,1H), imidazo[4,5- 6.28 (s, 1H), 4.91 (m, 1H), 3.64 (t, J = 6.0 Hz, 1H),b]pyridin-5-ylamino]- 3.30 (m, 2H), 2.00 (m, 1H), 1.06 (m, 2H), 2-(4-0.70-0.80 (m, 2H). MS: Calcd.: 378; Found: [M + H]⁺ fluorophenyl)ethanol379 16 2-[3-(5-Cyclopropyl- (400 MHz) 12.49 (s, 1H), 8.20 (s, 1H), 7.71(d, J = 8.8 Hz, Method 1H-pyrazol-3-yl)-3H- 1H), 7.45 (m, 2H), 7.07 (m,2H), 51 imidazo[4,5- 6.75 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.55 (s,1H), b]pyridin-5-ylamino]- 4.86 (t, J = 5.2 Hz, 2H), 3.96 (m, 4H), 1.86(m, 2-(4-fluorophenyl) 1H), 1.00 (m, 2H), 0.60 (m, 2H). MS: Calcd.:propane-1,3-diol 408; Found: [M + H]⁺ 409 17 6-Chloro-3-(5- (400 MHz)12.65 (s, 1H), 8.36 (s, 1H), 8.05 (s, Method cyclopropyl-1H- 1H), 7.46(m, 2H), 7.10 (m, 2H), 5.80 (d, J = 6.8 Hz, 52 pyrazol-3-yl)-N-[(S)-1H), 6.21 (s, 1H), 5.17 (m, 1H), 1.99 (m, 1-(4-fluorophenyl) 1H), 1.56(d, J = 7.20 Hz, 3H), 1.06 (m, 2H), ethyl]-3H- 0.70-0.80 (m, 2H). MS:Calcd.: 396; Found: imidazo[4,5- [M + H]⁺ 397. b]pyridin-5-amine 18N-(4-Fluorobenzyl)-6- (400 MHz) 12.66 (s, 1H), 8.37 (s, 1H), 8.06 (s,Method chloro-3-(5- 1H), 7.40 (m, 3H), 7.11 (m, 2H), 6.20 (s, 1H), 53cyclopropyl-1H- 4.60 (d, J = 6.0 Hz, 1H), 1.94 (m, 1H), 1.01 (m,pyrazol-3-yl)-3H- 2H), 0.65 (m, 2H). MS: Calcd.: 382; Found:imidazo[4,5- [M + H]⁺ 383. b]pyridin-5-amine 19 (2R)-2-[6-Chloro-3- (400MHz) 12.64 (s, 1H), 8.38 (s, 1H), 8.09 (s, Method (5-cyclopropyl-1H-1H), 7.44 (m, 2H), 7.12 (m, 2H), 6.65 (d, J = 6.0 Hz, 54pyrazol-3-yl)-3H- 1H), 6.13 (s, 1H), 5.14 (t, J = 5.6 Hz, 1H),imidazo[4,5- 5.04 (m, 1H), 3.69-3.80 (m, 2H), 1.98 (m, 1H),b]pyridin-5-ylamino]- 1.06 (m, 2H), 0.70-0.80 (m, 2H). MS: Calcd.: 2-(4-412; Found: [M + H]⁺ 413. fluorophenyl)ethanol 20 (2R)-2-[6-Chloro-3-(400 MHz) 12.57 (s, 1H), 8.39 (s, 1H), 8.10 (s, Method (5-methyl-1H-1H), 7.46 (m, 2H), 7.13 (m, 2H), 6.63 (d, J = 5.2 Hz, 55pyrazol-3-yl)-3H- 1H), 6.15 (s, 1H), 5.16 (t, J = 5.6 Hz, 1H),imidazo[4,5- 4.99 (m, 1H), 3.67-3.79 (m, 2H), 2.31 (s, 3H).b]pyridin-5-ylamino]- MS: Calcd.: 386; Found: [M + H]⁺ 387.2-(4-fluorophenyl) ethanol 21 3-(5-Isopropoxy-1H- (400 MHz) 12.38 (s,1H), 8.49 (d, J = 4.0 Hz, Method pyrazol-3-yl)-N-((S)- 1H), 8.27 (s,1H), 7.75 (d, J = 8.8 Hz, 1H), 56 1-(pyridin-2-yl)ethyl)- 7.67 (m, 1H),7.44 (d, J = 6.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 3H-imidazo[4,5- 1H), 7.20(m, 1H), 6.63 (d, J = 8.8 Hz, 1H), b]pyridin-5-amine 6.02 (s, 1H), 5.06(m, 1H), 4.49 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.0 Hz,3H), 1.35 (d, J = 5.6 Hz, 3H). MS: Calcd.: 363; Found: [M + H]⁺ 364. 22N-((S)-1-(4- (400 MHz) 12.42 (s, 1H), 8.26 (s, 1H), 7.73 (d, J = 8.8 Hz,Method Fluorophenyl)ethyl)- 1H), 7.42 (m, 2H), 7.36 (d, J = 6.8 Hz, 573-(5-isopropoxy-1H- 1H), 7.09 (m 2H), 6.58 (d, J = 8.8 Hz, 1H),pyrazol-3-yl)-3H- 5.99 (s, 1H), 5.04 (m, 1H), 4.46 (m, 1H), 1.46 (d, J =6.8 Hz, imidazo[4,5- 3H), 1.40 (d, J = 6.0 Hz, 3H), 1.33 (d, J = 6.0 Hz,b]pyridin-5-amine 3H). MS: Calcd.: 380; Found: [M + H]⁺ 381. 23(2R)-2-(4- (400 MHz) 12.43 (b, 1H), 8.26 (s, 1H), 7.74 (d, J = 8.8 Hz,Method Fluorophenyl)-2-(3- 1H), 7.42 (m, 2H), 7.30 (d, J = 6.8 Hz, 58(5-isopropoxy-1H- 1H), 7.10 (m, 2H), 6.64 (d, J = 8.8 Hz, 1H),pyrazol-3-yl)-3H- 6.01 (s, 1H), 5.00 (t, J = 6.4 Hz, 1H), 4.95 (m, 1H),imidazo[4,5- 3.67 (m, 2H), 1.41 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.0Hz, b]pyridin-5- 3H). MS: Calcd.: 396; Found: [M + H]⁺ ylamino)ethanol397. 24 6-Chloro-N-((S)-1-(4- (400 MHz) 12.52 (s, 1H), 8.39 (s, 1H),8.08 (s, Method fluorophenyl)ethyl)-3- 1H), 7.46 (m, 2H), 7.09 (m, 2H),6.83 (d, J = 7.2 Hz, 59 (5-isopropoxy-1H- 1H), 5.95 (s, 1H), 5.23 (m,1H), 4.49 (m, pyrazol-3-yl)-3H- 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.41 and1.34 (d, J = 6.0 Hz, imidazo[4,5- 6H). MS: Calcd.: 414; Found: [M + H]⁺b]pyridin-5-amine 415. 25 3-(5-Cyclopropyl-1H- (400 MHz) 12.56 (s, 1H),8.54 (d, J = 4.8 Hz, Method pyrazol-3-yl)-N-((S)- 1H), 8.26 (s, 1H),7.74 (d, J = 8.8 Hz, 1H), 60 1-(pyridin-2-yl)ethyl)- 7.67 (m, 1H), 7.43(d, J = 6.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 3H-imidazo[4,5- 1H), 7.20 (m,1H), 6.62 (d, J = 8.8 Hz, 1H), b]pyridin-5-amine 6.22 (s, 1H), 5.01 (m,1H), 1.97 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.03 (m, 2H), 0.81-0.70 (m,2H). MS: Calcd.: 345; Found: [M + H]⁺ 346. 26 (2R)-2-(4- (400 MHz) 12.53(b, 1H), 8.27 (s, 1H), 7.73 (d, J = 8.8 Hz, Method Fluorophenyl)-2-(3-1H), 7.44 (m, 2H), 7.24 (d, J = 6.8 Hz, 61 (5-methyl-1H- 1H), 7.13 (m,2H), 6.62 (d, J = 8.8 Hz, 1H), pyrazol-3-yl)-3H- 6.34 (s, 1H), 4.96 (t,J = 5.6 Hz, 1H), 4.91 (m, 1H), imidazo[4,5- 3.65 (m, 2H), 2.32 (s, 3H).MS: Calcd.: 352; b]pyridin-5- Found: [M + H]⁺ 353. ylamino)ethanol

Example 273-(5-Cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-benzo[d]imidazol-5-amine

A mixture of(S)—N³-(5-cyclopropyl-1H-pyrazol-3-yl)-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine(Method 62; 0.395 g, 1.12 mmol) and formamidine acetate (0.234 g, 2.25mmol) in EtOH (5 ml) was heated at reflux for 2 hrs. After cooling to25° C., the reaction mixture was treated with saturated sodiumbicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer wasseparated, washed with brine (10 ml), and dried over Na₂SO₄. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (EtOAc) to give the title compound as an off-whitesolid (0.205 g, 50%). NMR (400 MHz) 12.65 (s, 1H), 8.17 (s, 1H), 7.43(m, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.10 (m, 2H), 6.90 (s, 1H), 6.62 (d,J=8.8 Hz, 1H), 6.25 (d, J=6.4 Hz, 1H), 6.08 (s, 1H), 4.51 (m, 1H), 1.96(m, 1H), 1.43 (d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.:361. Found: [M+H]⁺ 362.

Examples 28-32

Following a similar procedure to Example 27, the following compoundswere synthesized from a suitable aminobenzene by treatment withformamidine acetate.

Ex. Compound NMR/MS SM 28 (2R)-2-[3-(5- (400 MHz) 12.65 (s, 1H), 8.18(s, 1H), 7.44 (m, Method Cyclopropyl-1H- 2H), 7.34 (d, J = 8.8 Hz, 1H),7.11 (m, 2H), 63 pyrazol-3-yl)-3H- 6.92 (s, 1H), 6.65 (d, J = 8.8 Hz,1H), 6.08 (s, 1H), benzo[d]imidazol-5- 6.07 (d, J = 5.6 Hz, 1H), 4.95(t, J = 5.6 Hz, 1H), ylamino]-2-(4- 4.40 (m, 1H), 3.61 (t, J = 5.6 Hz,2H), 1.95 (m, 1H), fluorophenyl)ethanol 1.01 (m, 2H), 0.76 (m, 2H). MS:Calcd.: 377; Found: [M + H]⁺ 378. 29 N-(4-Fluorobenzyl)- (400 MHz) 12.66(s, 1H), 8.21 (s, 1H), 7.42 (m, Method 3-(5-cyclopropyl- 2H), 7.38 (d, J= 8.8 Hz, 1H), 7.12 (m, 2H), 64 1H-pyrazol-3-yl)- 7.04 (s, 1H), 6.66 (d,J = 8.8 Hz, 1H), 6.32 (t, J = 6.0 Hz, 3H- 1H), 6.20 (s, 1H), 4.28 (d, J= 4.8 Hz, 2H), benzo[d]imidazol-5- 1.96 (m, 1H), 0.99 (m, 2H), 0.75 (m,2H). MS: amine Calcd.: 347; Found: [M + H]⁺ 348. 30 N-[(S)-1-(4- (400MHz) 12.45 (s, 1H), 8.18 (s, 1H), 7.42 (m, Method Fluorophenyl)ethyl]-2H), 7.34 (d, J = 8.4 Hz, 1H), 7.09 (m, 2H), 65 3-(5-isopropoxy-1H- 6.93(s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 6.4 Hz,pyrazol-3-yl)-3H- 1H), 5.88 (s, 1H), 4.50 (m, 2H), 1.43 (d, J = 6.8 Hz,benzo[d]imidazol-5- 3H), 1.36 (m, 6H). MS: Calcd.: 379; amine Found:[M + H]⁺ 380. 31 3-(5-Cyclopropyl- (400 MHz) 12.68 (s, 1H), 8.52 (d, J =4.4 Hz, 1H), Method 1H-pyrazol-3-yl)-N- 8.18 (s, 1H), 7.69 (m, 1H), 7.40(d, J = 7.6 Hz, 67 ((S)-1-(pyridin-2- 1H), 7.35 (d, J = 8.8 Hz, 1H),7.21 (m, 1H), yl)ethyl)-3H- 6.91 (s, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.34(d, J = 6.8 Hz, benzo[d]imidazol-5- 1H), 6.10 (d, J = 1.6 Hz, 1H), 4.53(m, 1H), amine 1.96 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.03 (m, 2H),0.76 (m, 2H). MS: Calcd.: 344; Found: [M + H]⁺ 345. 32 (2R)-2-(4- (400MHz) 12.61 (s, 1H), 8.22 (s, 1H), 7.44 (m, Method Fluorophenyl)-2-(3-2H), 7.35 (d, J = 8.8 Hz, 1H), 7.12 (m, 2H), 68 (5-methyl-1H- 6.98 (s,1H), 6.64 (d, J = 8.4 Hz, 1H), 6.19 (s, 1H), pyrazol-3-yl)-3H- 6.11 (d,J = 6.0 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), benzo[d]imidazol-5- 4.40 (m,1H), 3.61 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H). MS: ylamino)ethanol Calcd.:351; Found: [M + H]⁺ 352.

Example 331-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carbonitrile

A mixture of(S)-5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]benzonitrile(Method 69; 3.85 g, 10.2 mmol) and formamidine acetate (2.13 g, 20.5mmol) in EtOH (50 ml) was heated at reflux for 2 hrs. After cooling, thereaction mixture was treated with saturated sodium bicarbonate solution(10 ml) and EtOAc (30 ml). The organic layer was separated, washed withbrine (10 ml), and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by column chromatography(EtOAc:MeOH=30:1) to give the title compound as an off-white solid (3.23g, 82%). NMR (400 MHz) 12.79 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.53(m, 2H), 7.14 (m, 2H), 7.01 (s, 1H), 6.10 (s, 1H), 6.09 (d, J=7.6 Hz,1H), 4.63 (m, 1H), 1.97 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.03 (m, 2H),0.76 (m, 2H). MS: Calcd.: 386. Found: [M+H]⁺ 387.

Example 341-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carboxamide

1-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carbonitrile(Example 33; 0.30 g, 0.77 mmol) was dissolved in MeOH (10 ml), followedby addition of 25% aqueous KOH solution (0.87 ml, 3.88 mol) and 15 dropsof 30% H₂O₂ solution. The reaction was heated at 75° C. for 48 hours.After cooling, the reaction was diluted with H₂O (5 ml). The resultedsolid was collected by filtration and dried under vacuum to give thetitle compound (0.137 g, 44%) as a white solid. NMR (400 MHz) 12.70 (s,1H), 8.66 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 8.03 (br, 1H),7.42 (m, 2H), 7.24 (br, 1H), 7.13 (m, 1H), 6.80 (s, 1H), 6.00 (s, 1H),4.57 (m, 1H), 1.95 (m, 1H), 1.47 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74(m, 2H). MS: Calcd.: 404. Found: [M+H]⁺ 405.

Example 35

Following a similar procedure to Example 33, the following compoundswere synthesized from a suitable aminobenzene by treatment withformamidine acetate.

Ex. Compound NMR/MS SM 35 1-(5-Cyclopropyl-1H- (400 MHz) 12.77 (s, 1H),8.45 Method pyrazol-3-yl)-6-[(R)-1- (s, 1H), 7.99 (s, 1H), 7.49 (m, 70(4-fluorophenyl)-2- 2H), 7.15 (m, 2H), 6.95 (s, 1H), hydroxyethylamino]-6.06 (s, 1H), 5.95 (d, J = 4.8 Hz, 1H-benzo[d]imidazole- 1H), 5.32 (t, J= 4.8 Hz, 5-carbonitrile 1H), 3.79 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H),1.97 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H). MS: Calcd.: 402; Found: [M +H]⁺ 403.

Example 363-(5-Cyclopropyl-1H-pyrazol-3-yl)-4-fluoro-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-benzo[d]imidazol-5-amine

A mixture of(S)—N³-(5-cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine(Method 71; 0.370 g, 1.00 mmol) and formamidine acetate (0.209 g, 2.00mmol) in EtOH (10 ml) was heated at reflux for 1 hour. After cooling,the reaction mixture was treated with saturated sodium bicarbonatesolution (5 ml) and EtOAc (15 ml). The organic layer was separated,washed with brine (3 ml), and dried over Na₂SO₄. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (hexane:EtOAc=1:1) to give the title compound as anoff-white solid (0.125 g, 33%). NMR (400 MHz) 12.79 (s, 1H), 8.08 (s,1H), 7.45 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 6.60(t, J=8.2 Hz, 1H), 6.19 (s, 1H), 5.68 (d, J=7.2 Hz, 1H), 4.65 (m, 1H),1.98 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.01 (m, 2H), 0.77 (m, 2H). MS:Calcd.: 379. Found: [M+H]⁺ 380.

Example 37

Following a similar procedure to Example 36, the following compound wassynthesized from a suitable aminobenzene by treatment with formamidineacetate.

Ex. Compound NMR/MS SM 37 (2R)-2-[3-(5- (400 MHz) 12.78 (s, 1H), 8.09Method Cyclopropyl-1H- (s, 1H), 7.44 (m, 2H), 7.20 (d, 72pyrazol-3-yl)-4- J = 8.8 Hz, 1H), 7.12 (t, fluoro-3H- J = 9.0 Hz, 2H),6.51 (t, benzo[d]imidazol-5- J = 8.2 Hz, 1H), 6.21 (s, 1H),ylamino]-2-(4- 5.50 (d, J = 4.4 Hz, 1H), 5.07 (t, fluorophenyl)ethanol J= 5.8 Hz, 1H), 4.51 (q, J = 6.0 Hz, 1H), 3.58-3.70 (m, 2H), 1.98 (m,1H), 1.00 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 395; Found: [M + H]⁺ 396.

Example 383-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-benzo[d]imidazol-5-amine

A mixture of(S)—N³-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine(Method 73; 0.302 g, 0.816 mmol) and formamidine acetate (0.170 g, 1.63mmol) in EtOH (10 ml) was heated at reflux for 1 hr. After cooling, thereaction mixture was treated with saturated sodium bicarbonate solution(5 ml) and EtOAc (15 ml). The organic layer was separated, washed withbrine (3 ml), and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:1) to give the title compound as an off-white solid(0.170 g, 55%). NMR (400 MHz) 12.69 (s, 1H), 8.27 (s, 1H), 7.47 (m, 2H),7.39 (d, J=12.0 Hz, 1H), 7.12 (t, J=9.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H),6.07 (s, 1H), 5.90 (d, J=4.8 Hz, 1H), 4.56 (m, 1H), 1.96 (m, 1H), 1.51(d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 379. Found:[M+H]⁺380.

Example 39

Following a similar procedure to Example 38, the following compoundswere synthesized from a suitable aminobenzene by treatment withformamidine acetate.

Ex. Compound NMR/MS SM 39 (2R)-2-[3-(5- (400 MHz) 12.69 (s, 1H), 8.29Method Cyclopropyl-1H- (s, 1H), 7.47 (m, 3H), 7.14 (t, 74pyrazol-3-yl)-6-fluoro- J = 8.8 Hz, 2H), 6.93 (d, 3H-benzo[d]imidazol- J= 8.0 Hz, 1H), 6.03 (s, 1H), 5-ylamino]-2-(4- 5.70 (br, 1H), 5.18 (t, J= 5.8 Hz, fluorophenyl)ethanol 1H), 4.45 (m, 1H), 3.62-3.73 (m, 2H),1.95 (m, 1H), 1.02 (m, 2H), 0.74 (m, 2H). MS: Calcd.: 395; Found: [M +H]⁺ 396.

Example 401-(5-Cyclopropyl-1H-pyrazol-3-yl)-N—((S)-1-(4-fluorophenyl)ethyl)-1H-imidazo[4,5-c]pyridin-6-amine

A mixture of(S)—N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,4,5-triamine(Method 88, 0.15 g, 0.43 mmol) and formamidine acetate (0.089 g, 0.85mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to25° C., the reaction mixture was treated with saturated NaHCO₃ solution(10 ml) and EtOAc (30 ml). The organic layer was separated, washed withbrine (10 ml), and dried over sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc-MeOH=40:1) to give the title compound as anoff-white solid (0.092 g, 60%). ¹H NMR (400 MHz) 12.75 (s, 1H), 8.39 (s,1H), 8.33 (s, 1H), 7.42 (m, 2H), 7.08 (m, 2H), 6.90 (s, 1H), 6.89 (d,J=2.8 Hz, 1H), 6.26 (d, J=1.6 Hz, 1H), 5.00 (m, 1H), 1.96 (m, 1H), 1.42(d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 362. Found:[M+H]⁺363.

Example 41(2R)-2-(1-(5-Cyclopropyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-6-ylamino)-2-(4-fluorophenyl)ethanol

A mixture of(R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 93, 0.14 g, 0.38 mmol) and formamidine acetate (0.079 g, 0.76mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to25° C., the reaction mixture was treated with saturated NaHCO₃ solution(10 ml) and EtOAc (30 ml). The organic layer was separated, washed withbrine (10 ml), and dried over sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc-MeOH=20:1) to give the title compound as anoff-white solid (0.22 g, 32%). ¹H NMR (400 MHz) 12.76 (s, 1H), 8.40 (s,1H), 8.34 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.92 (s, 1H), 6.72 (d,J=7.2 Hz, 1H), 6.25 (s, 1H), 4.92 (m, 2H), 3.62 (m, 2H), 1.97 (m, 1H),1.02 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 378. Found: [M+H]⁺ 379.

Example 426-(Aminomethyl)-3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—((S)-1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine

To1-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-carbonitrile(Example 33, 1.25 g, 3.2 mmol) and 10% palladium on carbon (0.69 g, 0.65mmol) in MeOH (40 ml) was added 15 drops of conc. HCl. The reaction wascharged 45 psi hydrogen and shook for 30 hours. The solvent was removed.The residue was dissolved in EtOAc (200 ml), washed with saturatedsodium bicarbonate (50 ml) and dried over sodium sulfate. After removalof solvent, the residue was purified by reverse-phase columnchromatography (5-50% CH₃CN in H₂O) to give the title compound as anoff-white solid (0.81 g, 61%). ¹H NMR (400 MHz) 12.65 (s, 1H), 8.15 (s,1H), 7.46 (m, 2H), 7.36 (s, 1H), 7.11 (m, 2H), 6.91 (d, J=5.6 Hz, 1H),6.74 (s, 1H), 5.94 (s, 1H), 4.54 (m, 1H), 3.92 (s, 2H), 2.07-1.91 (m,3H), 1.48 (d, J=6.4 Hz, 3H), 1.01 (m, 2H), 0.72 (m, 2H). MS: Calcd.:390. Found: [M+H]⁺ 391.

Example 43N-((1-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-yl)methyl)acetamide

A round bottom flask was charged with6-(aminomethyl)-3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—((S)-1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine(Example 42; 0.10 g, 0.256 mmol) and acetic acid loaded TFP resin (1.0mmol/g loading, 0.256 g, 0.256 mmol) in mixture of THF-DCM (1:1, 3 ml)at 0° C. The resulting solution was stirred vigorously at 0° C. for 1hour and filtered through a Jones tube. The resulting resin was washedwith a THF-DCM solution (1:1, 3×5 ml). After removal of solvent, theresidue was purified by column chromatography (EtOAc-MeOH=20:1) to givethe title compound as an off-white solid (0.083 g, 75%). ¹H NMR (400MHz) 12.67 (s, 1H), 8.50 (m, 1H), 8.18 (s, 1H), 7.39 (m, 3H), 7.11 (m,2H), 6.73 (s, 1H), 6.09 (d, J=6.0 Hz, 1H), 5.96 (s, 1H), 4.53 (m, 1H),4.42 (m, 1H), 4.31 (m, 1H), 1.93 (m, 1H), 1.93 (s, 3 h), 1.47 (d, J=6.4Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 432. Found: [M+H]⁺ 433.

Example 441-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazole-4-carbonitrile

The mixture of(S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzonitrile(Method 96, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol) inEtOH (50 ml) was heated at reflux for 36 hours. After cooling, thereaction mixture was treated with saturated sodium bicarbonate solution(30 ml) and EtOAc (80 ml). The organic layer was separated, washed withbrine (30 ml), and dried over sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc) to give the title compound as an off-white solid(1.05 g, 26%). ¹H NMR (400 MHz) 12.80 (s, 1H), 8.45 (s, 1H), 7.43 (m,2H), 7.31 (d, J=2.0 Hz, 1H), 7.12 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.75(d, J=6.8 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 4.58 (m, 1H), 1.97 (m, 1H),1.44 (d, J=6.4 Hz, 3H), 1.03 (m, 2H), 0.75 (m, 2H). MS: Calcd.: 386.Found: [M+H]⁺ 387.

Example 451-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-4-carboxamide

The mixture of(S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzamide(Method 100, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol)in EtOH (50 ml) was heated at reflux for 36 hours. After cooling, thereaction mixture was treated with saturated sodium bicarbonate solution(30 ml) and EtOAc (80 ml). The organic layer was separated, washed withbrine (30 ml), and dried over sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc-MeOH=30:1) to give the title compound as anoff-white solid (0.45 g, 11%). ¹H NMR (400 MHz) 12.79 (s, 1H), 9.00 (d,J=2.8 Hz, 1H), 8.42 (s, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.43 (m, 2H), 7.38(d, J=2.0 Hz, 1H), 7.09 (m, 3H), 6.59 (d, J=6.4 Hz, 1H), 6.16 (d, J=1.6Hz, 1H), 4.54 (m, 1H), 1.97 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.02 (m,2H), 0.76 (m, 2H). MS: Calcd.: 404. Found: [M+H]⁺ 405.

Example 463-(5-Cyclopropyl-1H-pyrazol-3-yl)-4,6-difluoro-N—((S)-1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine

(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluoro-N¹-(1-(4-fluorophenyl)ethyl)benzene-1,3,4-triamine(Method 101, 0.278 g, 0.718 mmol) and formamidine acetate (0.149 g, 1.44mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodiumbicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organiclayer was separated, washed with brine (3 ml) and dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by chromatography (Hex-EtOAc=1:1) to give the titlecompound as off white solid (0.120 g, 42%). ¹H NMR (400 MHz) 12.83 (s,1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.31 (d, J=11.2 Hz, 1H), 7.06 (t, J=8.8Hz, 2H), 6.15 (s, 1H), 5.15 (d, J=10.4 Hz, 1H), 4.67 (m, 1H), 1.98 (m,1H), 1.46 (d, J=6.8 Hz, 3H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.:397. Found: [M+H]⁺ 398.

Example 47(2R)-2-(3-(5-Cyclopropyl-1H-pyrazol-3-yl)-4,6-difluoro-3H-benzo[d]imidazol-5-ylamino)-2-(4-fluorophenyl)ethanol

(R)-2-(4-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluorophenylamino)-2-(4-fluorophenyl)ethanol(Method 104, 0.230 g, 0.57 mmol) and formamidine acetate (0.119 g, 1.14mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodiumbicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organiclayer was separated, washed with brine (3 ml) and dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by chromatography (Hex-EtOAc=1:1) to give the titlecompound as off white solid (0.070 g, 30%). ¹H NMR (400 MHz) 12.83 (s,1H), 8.20 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.8 Hz, 2H), 6.14 (s, 1H),5.14 (d, J=9.6 Hz, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.62 (m, 1H), 3.64-3.74(m, 2H), 1.97 (m, 1H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 413.Found: [M+H]⁺ 414.

Example 48N-(1,3-Benzodioxol-5-ylmethyl)-3-(5-cyclopropyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine

A mixture of6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 77, 70 mg, 0.25 mmol), piperonylamine (54 mg, 0.36 mmol),saturated NaHCO₃ (0.5 ml), and anhydrous 1,4-dioxane (0.5 ml) was heatedat 100° C. for 3 hours. The reaction was allowed to cool to roomtemperature, and the solvents were evaporated in a Genevac. Theresulting residue was treated with zinc dust (195 mg, 2.98 mmol), formicacid (140 μL, 3.71 mmol), and 1,4-dioxane (0.5 ml), and the resultingmixture was reheated to 100° C. After 4 hours of heating, the reactionwas allowed to cool and the volatile components were evaporated using aGenevac. The concentrated reaction mixture was treated with MeOH (1 ml),DCM (1 ml), and Na₂CO₃ (125 mg). This mixture was allowed to stir atroom temperature for 45 minutes, at which point the entire mixture wasloaded on top of a short column of silica gel (˜3 cm long×1.5 cmdiameter). The column was flushed with MeOH (˜15 ml), and the eluent wasconcentrated in a Genevac. The title compound was obtained from theresidue by crystallization from CHCl₃/MeOH (7.2 mg). ¹H NMR (400 MHz)0.65-0.76 (m, 2H), 0.99 (m, 2H), 1.96 (m, 1H), 4.41 (m, 2H), 5.94 (s,2H), 6.45 (s, 1H), 6.52 (m, 1H), 6.75 (m, 1H), 6.83 (m, 1H), 6.92 (m,1H), 7.35 (m, 1H), 7.71 (m, 2H), 8.27 (s, 1 H), 12.60 (s, 1H). MS:Calcd.: 374. Found: [M+H]⁺ 375.

Examples 49-54

Following a similar procedure to Example 48, the following compoundswere synthesized from a suitable pyridine.

Ex Compound NMR/MS SM 49 3-(5-Cyclopropyl- ¹H NMR (400 MHz) 0.61-0.71(m, 2 H) Method 1H-pyrazol-3-yl)-N- 0.96 (m, 2 H) 1.91 (m, 1 H) 4.61 (m,2 H) 6.32 (s, 1 H) 77 [3- 6.57 (m, 1 H) 7.49-7.60 (m, 2 H) 7.67 (m, 1 H)(trifluoromethyl)benzyl]- 7.71 (m, 1 H) 7.76 (m, 1 H) 8.28 (s, 1 H)12.59 (s, 3H-imidazo[4,5- 1 H). MS: Calcd.: 398; Found: [M + H]⁺ 399.b]pyridin-5-amine 50 3-(5-Cyclopropyl- ¹H NMR (400 MHz) 0.65 (m, 2 H)Method 1H-pyrazol-3-yl)-N- 0.94-1.04 (m, 2 H) 1.92 (m, 1 H) 4.48 (m, 2H) 6.29 (s, 1 H) 77 (3,4-difluorobenzyl)- 6.55 (m, 1 H) 7.19 (m, 1 H)7.33-7.40 (m, 1 H) 3H-imidazo[4,5- 7.46 (m, 1 H) 7.75 (m, 1 H) 8.27 (s,1 H) 12.60 (s, b]pyridin-5-amine 1 H). MS: Calcd.: 366; Found: [M + H]⁺367. 51 3-(5-Cyclopropyl- ¹H NMR (400 MHz) 0.75 (m, 2 H) 0.92 (m, 3 H)Method 1H-pyrazol-3-yl)-N- 1.06 (m, 2 H) 1.72 (m, 1 H) 1.84 (m, 1 H) 77((1S)-1- 1.92-2.03 (m, 1 H) 4.74 (m, 1 H) 6.34 (s, 1 H) 6.58 (m,phenylpropyl)-3H- 1 H) 7.18 (m, 2 H) 7.24-7.33 (m, 3 H) imidazo[4,5-7.34-7.41 (m, 12 H) 7.69 (m, 1 H) 8.24 (s, 1 H), b]pyridin-5-amine 12.60(s, 1H). MS: Calcd.: 358; Found: [M + H]⁺ 359. 52 3-(5-Cyclopropyl- ¹HNMR (400 MHz) 0.61-0.69 (m, 2 H) Method 1H-pyrazol-3-yl)-N- 0.84-0.94(m, 2 H) 1.90 (m, 1 H) 3.00 (m, 2 H) 3.60 (s, 77 [2-(1H-indol-3- 2 H)6.48 (m, 1 H) 6.64 (s, 1 H) 6.94 (m, 1 H) yl)ethyl]-3H- 7.05 (m, 1 H)7.18 (s, 1 H) 7.33 (m, 1 H) 7.53 (m, imidazo[4,5- 1 H) 7.71 (m, 1 H)8.22 s, 1 H) 10.82 (s, 1 H) b]pyridin-5-amine 12.60 (s, 1 H). MS:Calcd.: 383; Found: [M + H]⁺ 384. 53 3-(5-Cyclopropyl- ¹H NMR (400 MHz)0.73 (m, 2 H) Method 1H-pyrazol-3-yl)-N- 0.92-1.02 (m, 2 H) 1.97 (m, 1H) 3.02-3.11 (m, 2 H) 77 (2-pyridin-2-ylethyl)- 3.62-3.72 (m, 2 H) 6.47(m, 1 H) 6.70 (s, 1 H) 3H-imidazo[4,5- 6.94-7.03 (m, 1 H) 7.22 (m, 1 H)7.29 (m, 1 H) b]pyridin-5-amine 7.67-7.77 (m, 2 H) 8.31 (s, 1 H) 8.53(m, 1 H) 12.64 (s, 1 H). MS: Calcd.: 345; Found: [M + H]⁺ 346. 542-{[3-(5- ¹H NMR (400 MHz) 0.77 (m, 2 H) 0.94 (d, J = 6.8 Hz, MethodCyclopropyl-1H- 34 H) 1.03 (m, 2 H) 1.98-2.09 (m, 1 H) 77pyrazol-3-yl)-3H- 4.20 (m, 1 H) 4.89-4.99 (m, 1 H) 5.30 (m, 1 H)imidazo[4,5- 6.57 (m, 1 H) 6.62 (s, 1 H) 6.77 (m, 1 H) 7.21 (m, 2 H)b]pyridin-5- 7.33 (m, 2 H) 7.38-7.47 (m, 1 H) 7.72 (m, 1 H) yl]amino}-1-8.25 (s, 1 H) 12.69 (s, 1 H). MS: Calcd.: 374; phenylpropan-1-ol Found:[M + H]⁺ 375.

Preparation of Starting Materials: Method 1(R)-2-[4-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-6-methyl-5-nitropyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol

A solution of2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-nitropyrimidin-4-amine(Method 75; 1.0 g, 3.4 mmol), DIEA (0.57 g, 4.4 mmol), and(R)-2-amino-2-(4-fluorophenyl)ethanol (0.58 g, 3.7 mmol) in n-BuOH (15ml) was heated to 60° C. for 2 hours. The reaction was then cooled to25° C., concentrated, and treated with hexane. The resulting solid wascollected by filtration to give the title compound (1.3 g, 93%). MS:Calcd.: 413. Found: [M+H]⁺ 414.

Methods 2-7

Following a similar procedure to Method 1, the following compounds weresynthesized from2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine(Method 76) or2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine(Method 87) and the appropriate amine.

Meth Product NMR/MS Amine 2 N⁴-(5-Cyclopropyl- 0.62 (m, 2H), 0.95 (m,2H), 1.49 (m, [(1S)-1-(4- 1H-pyrazol-3-yl)-N²- 3H), 1.90 (m, 1H), 5.12(m, 1H), fluorophenyl) [(1S)-1-(4- 6.13 (s, 1H), 7.15 (m, 2H), 7.37 (m,2H), ethyl]amine fluorophenyl) ethyl]- 8.97 (s, 1H), 10.40 (s, 1H). MS:5-nitro pyrimidine- Calcd.: 383; Found: [M + H]⁺ 384.17 2,4-diamine 3(2R)-2-({4-[(5- 0.68 (m, 2H), 0.98 (m, 2H), 1.93 (m, (2R)-2-amino-2-Cyclopropyl-1H- 3H), 3.67 (m, 2H), 5.02 (m, 1H), (4-fluorophenyl)ethanolpyrazol-3-yl)amino]- 6.20 (s, 1H), 7.19 (m, 2H), 7.37 (m, 2H),5-nitropyrimidin-2- 8.97 (s, 1H), 10.40 (s, 1H), 12.36 (bryl}amino)-2-(4- s, 1H). MS: Calcd.: 399; Found: fluorophenyl)ethanol[M + H]⁺ 400.20 4 N⁴-(5-Cyclopropyl- 0.68 (m, 2H), 0.80 (m, 2H), 1.75(m, (4-fluorobenzyl)amine 1H-pyrazol-3-yl)-N²- 3H), 4.51 (m, 2H), 6.05(s, 1H), (4-fluorobenzyl)-5- 7.09 (m, 2H), 7.30 (m, 2H), 8.97 (s, 1H),nitropyrimidine-2,4- 10.40 (s, 1H), MS: Calcd.: 369; diamine Found: [M +H]⁺ 370.16 5 N⁴-(5-Cyclopropyl- 0.63 (m, 2H), 0.95 (m, 2H), 1.49 (m,[(1R)-1-(4- 1H-pyrazol-3-yl)-N²- 3H), 1.90 (m, 1H), 5.11 (m, 1H),fluorophenyl) [(1R)-1-(4- 6.14 (s, 1H), 7.15 (m, 2H), 7.37 (m, 2H),ethyl]amine fluorophenyl) ethyl]- 8.97 (s, 1H), 10.40 (s, 1H). MS:5-nitro pyrimidine- Calcd.: 383; Found: [M + H]⁺ 384.23 2,4-diamine 6(R)-2-(4- MS: Calcd.: 373; Found: [M + H]⁺ 374 (R)-2-amino-2-(4-Fluorophenyl)-2-(4- fluorophenyl)ethanol (5-methyl-1H-pyrazol-3-ylamino)- 5-nitropyrimidin-2- ylamino)ethanol 7 (S)-N²-(1-(4-(400 MHz) 12.23, 11.99 and 11.69 (s, (S)-1-(4-fluoro-Fluorophenyl)ethyl)- 1H), 10.52, 10.48 and 10.37 (s, 1H), phenyl)-N⁴-(5-isopropoxy- 9.15 and 9.97 (d, J = 7.2 Hz, 1H), ethylamine1H-pyrazol-3-yl)-5- 8.99 (s, 1H), 7.45-7.31 (m, 2H), nitropyrimidin-2,4-7.20-7.08 (m, 2H), 5.99, 5.85 and 5.77 (s, 1H), diamine 5.28, 5.18 and5.08 (m, 1H), 4.70, 4.63 and 4.32 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H),1.34-1.23 (m, 6H). MS: Calcd.: 401; Found: [M + H]⁺ 402.

Method 8(S)—N⁴-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]pyrimidine-2,4,5-triamine

To a suspension of(S)—N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]-5-nitropyrimidine-2,4-diamine(Method 9; 0.8 g, 2.0 mmol) and zinc dust (0.7 g, 10.0 mmol) in MeOH:THF(1:1, 50 ml) was slowly added saturated NH₄Cl solution (10 ml) at 25° C.After 3 hours, the reaction mixture was treated with saturated aqueousNH₄OAc solution (40 ml) and allowed to stir for 30 minutes. The reactionwas then filtered through a plug of celite with EtOAc (100 ml), and theresulting aqueous layer was extracted with EtOAc (2×100 ml), dried,filtered, and concentrated to give the title compound (0.04 g, 5%). MS:Calcd.: 353. Found: [M+H]⁺ 354.

Method 9(S)—N⁴-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]-5-nitropyrimidine-2,4-diamine

A mixture of2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine(Method 76; 1.0 g, 3.6 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.5 g,3.6 mmol), and DIEA (0.6 g, 4.6 mmol) in n-BuOH (15 ml) was stirred at25° C. for 1 hour and then concentrated. The resulting oil was purifiedby column chromatography (DCM:MeOH=50:1) to give the title compound (0.8g, 60%). MS: Calcd.: 383. Found: [M+H]⁺ 384.

Method 10 (S)-Ethyl6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitropyrimidine-4-carboxylate

A solution of ethyl2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidine-4-carboxylate(Method 11; 1.0 g, 2.8 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.43g, 3.1 mmol) in EtOH (20 ml) was stirred at 25° C. for 1 hour. Thereaction was concentrated, treated with water (50 ml), extracted withDCM (3×50 ml), dried, filtered, and concentrated. The residue was thenpurified by column chromatography (DCM:MeOH=50:1) to give the titlecompound (0.7 g, 53%). MS: Calcd.: 455. Found: [M+H]⁺ 456.

Method 11 Ethyl2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidine-4-carboxylate

To a THF (20 ml) solution of ethyl2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.0 g, 3.80 mmol) wasslowly added the 5-cyclopropyl-1H-pyrazol-3-amine (0.48 g, 3.85 mmol) inTHF (5 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes,treated with water (50 ml), and then extracted with DCM (3×50 ml),dried, filtered, and concentrated to give the title compound (1.2 g).MS: Calcd.: 352. Found: [M+H]⁺ 353.

Method 12(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]-3-nitropyridine-2,6-diamine

A mixture of6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 77; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.23g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heatedin a sealed tube at 165° C. for 18 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.41 g,99%). NMR (400 MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2 Hz,1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4 Hz,3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382. Found: [M+H]⁺ 383.

Methods 13-15

Following a similar procedure to Method 12, the following compounds weresynthesized from6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine(Method 77) and the appropriate amine.

Meth Product NMR/MS Amine 13 N⁶-(4-Fluorobenzyl)- (400 MHz) 12.24 (s,1H), 10.98 (s, 1H), (4- N²-(5-cyclopropyl- 8.29 (br, 1H), 8.11 (d, J =9.2 Hz, 1H), 7.36 (m, fluorobenzyl) 1H-pyrazol-3-yl)-3- 2H), 7.18 (m,2H), 6.20 (d, J = 9.6 Hz, 1H), amine nitropyridine-2,6- 6.19 (s, 1H),4.66 (d, J = 5.2 Hz, 2H), diamine 1.79 (m, 1H), 0.86 (m, 2H), 0.45 (m,2H). MS: Calcd.: 368; Found: [M + H]⁺ 369 14 (R)-2-[6-(5- (400 MHz)12.21 (s, 1H), 10.97 (s, 1H), (R)-2-amino- Cyclopropyl-1H- 8.74 (d, J =7.6 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 2-(4- pyrazol-3-ylamino)- 7.38(m, 2H), 7.18 (m, 2H), 6.31 (d, J = 9.2 Hz, fluorophenyl)5-nitropyridin-2- 1H), 6.20 (s, 1H), 5.21 (d, J = 5.6 Hz, ethanolylamino]-2-(4- 1H), 5.09 (t, J = 5.2 Hz, 1H), 3.64-3.75 (m,fluorophenyl)ethanol 2H), 1.91 (m, 1H), 0.98 (m, 2H), 0.66 (m, 2H). MS:Calcd.: 398; Found: [M + H]⁺ 399. 15 2-[6-(5-Cyclopropyl- (400 MHz)12.02 (s, 1H), 10.95 (s, 1H), 2-amino-2-(4- 1H-pyrazol-3- 8.07 (d, J =9.2 Hz, 1H), 7.93 (s, 1H), 7.35 (m, fluorophenyl) ylamino)-5- 2H), 7.14(m, 2H), 6.48 (d, J = 9.2 Hz, 1H), propane-1,3- nitropyridin-2- 5.04 (s,1H), 4.81 (s, 2H), 4.04 (m, 2H), diol ylamino]-2-(4- 3.90 (m, 2H), 1.68(m, 1H), 0.90 (m, 2H), fluorophenyl)propane- 0.51 (m, 2H). MS: Calcd.:428; Found: [M + H]⁺ 1,3-diol 429.

Method 16

(S)-3-Chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-[1-(4-fluorophenyl)ethyl]-5-nitropyridin-2,6-diamine

A mixture of5,6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridine-2-amine(Method 79; 0.26 g, 0.83 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.17g, 1.25 mmol), and DIEA (0.22 ml, 1.25 mmol) in n-BuOH (5 ml) was heatedin a sealed tube at 165° C. for 3 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:1) to give(S)-3-chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamineas a yellow solid (0.34 g, 99%). NMR (400 MHz) 12.29 (s, 1H), 10.68 (s,1H), 8.27 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.39 (m, 2H), 7.16 (m, 2H),6.11 (s, 1H), 5.42 (m, 1H), 1.89 (m, 1H), 1.60 (d, J=7.2 Hz, 3H), 0.95(m, 2H), 0.61 (m, 2H). MS: Calcd.: 416. Found: [M+H]⁺ 417.

Methods 17-25

Following a similar procedure to Method 16, the following compounds weresynthesized from the appropriate starting material and amine.

Meth Product NMR/MS SM Amine 2 17 N²-(4- (400 MHz) 12.29 (s, 1H), 10.73(s, Method (4-fluoro- Fluorobenzyl)-3- 1H), 8.70 (t, J = 6.0 Hz, 1H),8.12 (b, 79 phenyl)methanamine chloro-N⁶-(5- 1H), 7.30 (m, 2H), 7.16 (m,2H), cyclopropyl-1H- 6.02 (s, 1H), 4.71 (d, J = 6.0 Hz, 2H),pyrazol-3-yl)-5- 1.77 (m, 1H), 0.86 (m, 2H), 0.41 (m, 2H).nitropyridin-2,6- MS: Calcd.: 402; Found: [M + H]⁺ 403. diamine 18(R)-2-[3-Chloro- (400 MHz) 12.27 (s, 1H), 10.70 (s, Method 5-6-(5-cyclopropyl- 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.03 (d, 80cyclopropyl- 1H-pyrazol-3- J = 7.6 Hz, 1H), 7.39 (m, 2H), 1H-pyrazol-ylamino)-5- 7.14 (m, 2H), 6.15 (s, 1H), 5.31 (m, 1H), 3-aminenitropyridin-2- 5.13 (t, J = 4.8 Hz, 1H), 3.32-3.86 (m, ylamino]-2-(4-2H), 1.92 (m, 1H), 0.98 (m, 2H), fluorophenyl)ethanol 0.68 (m, 2H). MS:Calcd.: 432; Found: [M + H]⁺ 433. 19 (2R)-2-({3- (400 MHz) 12.23 (s,1H), 10.69 (s, Method 5-methyl-1H- Chloro-6-[(5- 1H), 8.30 (s, 1H), 8.00(d, J = 7.6 Hz, 80 pyrazol-3- methyl-1H- 1H), 7.41 (m 2H), 7.17 (m, 2H),amine pyrazol-3- 6.12-5.26 (m, 1H), 5.13 (t, J = 5.2 Hz, 1H),yl)amino]-5- 3.73-3.86 (m, 2H), 2.25 (s, 3H). MS: nitropyridin-2-Calcd.: 406; Found: [M + H]⁺ 407 yl}amino)-2-(4- fluorophenyl)ethanol 20(S)-N²-(5- (400 MHz) 12.10, 12.05 and 11.84 (s, Method (S)-1-Isopropoxy-1H- 1H), 10.96, 10.94 and 10.74 (s, 1H), 95 (pyridin-2-pyrazol-3-yl)-3- 9.09, 8.88 and 8.83 (d, J = 7.6 Hz, yl)- nitro-N⁶-(1-1H), 8.56 and 8.53 (m, 1H), 8.15 and ethylamine (pyridin-2- 8.11 (d, J =9.6 Hz, 1H), 7.77 (m, 1H), yl)ethyl)pyridine- 7.33 (m, 1H), 7.28 (m,1H), 6.28 and 2,6-diamine 6.07 (d, J = 9.6 Hz, 1H), 5.99 and 5.83 (s,1H), 5.78 and 5.77 (s, 1H), 5.35, 5.26 and 4.92 (m, 1H), 4.69, 4.68 and4.50 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.36 and 1.28 (m, 6H). MS:Calcd.: 383; Found: [M + H]⁺ 384. 21 (S)-N⁶-(1-(4- (400 MHz) 12.09,12.05 and 11.64 (s, Method (S)-1-(4- Fluorophenyl)ethyl)- 1H), 10.94,10.87 and 10.72 (s, 1H), 95 fluoro- N²-(5- 8.98, 8.76 and 8.70 (d, J =7.6 Hz, phenyl)- isopropoxy-1H- 1H), 8.16 and 8.11 (d, J = 9.6 Hz, 1H),ethylamine pyrazol-3-yl)-3- 7.45, 7.39 and 7.34 (m, 2H), 7.15 (m,nitropyridine-2,6- 2H), 6.24 and 6.04 (d, J = 9.6 Hz, 1H), diamine 6.03,5.88 and 5.76 (s, 1H), 5.32, 5.21 and 4.89 (m, 1H), 4.71, 4.59 and 4.27(m, 1H), 1.52 (m, 3H), 1.26 (m, 6H). MS: Calcd.: 400; Found: [M + H]⁺401. 22 (R)-2-(4- (400 MHz) 12.12, 12.10 and 11.61 (s, Method(R)-2-amino- Fluorophenyl)-2- 1H), 10.94, 10.87 and 10.74 (s, 1H), 952-(4- (6-(5-isopropoxy- 9.05, 8.82 and 8.73 (d, J = 7.2 Hz,fluorophenyl) 1H-pyrazol-3- 1H), 8.15 and 8.11 (d, J = 9.2 Hz, 1H),ethanol ylamino)-5- 7.45, 7.38 and 7.32 (m, 2H), 7.15 (m,nitropyridin-2- 2H), 6.32 and 6.07 (d, J = 9.2 Hz, 1H), ylamino)ethanol5.90, 5.83 and 5.79 (s, 1H), 5.32, 5.21 and 4.89 (m, 1H), 5.23 (m, 1H),5.12 (m, 1H), 4.78, 4.64 and 4.37 (m, 1H), 4.69 (m, 2H), 1.30 (m, 6H).MS: Calcd.: 416; Found: [M + H]⁺ 417. 23 (S)-3-Chloro-N²- (400 MHz)12.16 and 11.72 (s, 1H), Method (S)-1-(4- (1-(4- 10.64 and 10.58 (s,1H), 8.30 (m, 2H), 81 fluoro- fluorophenyl)ethyl)- 7.33 and 7.31 (m,2H), 7.16 and phenyl)- N⁶-(5- 7.08 (m, 2H), 5.81 and 5.71 (s, 1H), 5.48ethylamine isopropoxy-1H- and 5.33 (m, 1H), 4.60 and 4.21 (m,pyrazol-3-yl)-5- 1H), 1.61 and 1.57 (d, J = 6.8 Hz, 3H),nitropyridin-2,6- 1.26 (m, 6H). MS: Calcd.: 434; diamine Found: [M + H]⁺435. 24 (S)-N²-(5- (400 MHz) 12.24 (s, 1H), 11.01 (s, Method (S)-1-Cyclopropyl-1H- 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.56 (m, 77 (pyridin-2-pyrazol-3-yl)-3- 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.76 (m, yl)-nitro-N⁶-(1- 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 (m, ethylamine(pyridin-2- 1H), 6.28 (d, J = 9.2 Hz, 1H), 6.15 (s, yl)ethyl)pyridine-1H), 5.28 (m, 1H), 1.85 (m, 1H), 2,6-diamine 1.54 (d, J = 6.8 Hz, 3H),0.97 (m, 2H), 0.84 (m, 2H). MS: Calcd.: 365; Found: [M + H]⁺ 366. 25(R)-2-(4- (400 MHz) 12.18 (s, 1H), 10.96 (s, Method (R)-2-amino-Fluorophenyl)-2- 1H), 9.05, 8.79 (d, J = 7.2 Hz, 1H), 78 2-(4-(6-(5-methyl-1H- 8.09 (d, J = 9.2 Hz, 1H), 7.39 (m, 2H), fluorophenyl)pyrazol-3- 7.18 (m, 2H), 6.33 (d, J = 9.6 Hz, 1H), ethanol ylamino)-5-6.19 (s, 1H), 5.17 (m, 1H), 5.11 (t, J = 5.6 Hz, nitropyridin-2- 1H),3.68 (m, 2H), 2.24 (s, ylamino)ethanol 3H). MS: Calcd.: 372; Found: [M +H]⁺ 373.

Method 26(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-N¹-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine

A mixture of 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazol-3-amine(Method 82; 0.27 g, 1.03 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.72g, 5.15 mmol), and DIEA (0.27 ml, 1.54 mmol) in n-BuOH (5 ml) was heatedin a sealed tube at 230° C. for 23 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:2) to give the title compound as a yellow solid (0.38 g,97%). NMR (400 MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6 Hz,1H), 7.76 (d, J=6.4 Hz, 1H), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, 1H),6.22 (d, J=8.4 Hz, 1H), 5.60 (br, 1H), 4.57 (m, 1H), 1.87 (m, 1H), 1.44(d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.70 (m 2H). MS: Calcd.: 381. Found:[M+H]⁺ 382.

Methods 27-31

Following a similar procedure to Method 26, the following compounds weresynthesized from the appropriate starting materials.

Meth Product NMR/MS SM Amine 27 (R)-2-[3-(5- (400 MHz) 12.25 (s, 1H),10.14 (s, Method (R)-2- Cyclopropyl-1H- 1H), 7.87 (d, J = 9.6 Hz, 1H),7.72 82 amino-2-(4- pyrazol-3-ylamino)- (d, J = 6.8 Hz, 1H), 7.35 (m,2H), fluorophenyl)ethanol 4-nitrophenylamino]- 7.15 (m, 2H), 6.74 (br,1H), 6.27 2-(4- (br, 1H), 5.62 (br, 1H), 5.03 (t, J =fluorophenyl)ethanol 5.6 Hz, 1H), 4.46 (m, 1H), 3.62 (t, J = 5.6 Hz,2H), 1.89 (m, 1H), 0.97 (m, 2H), 0.71 (m 2H). MS: Calcd.: 397; Found:[M + H]⁺ 398. 28 N¹-(4- (400 MHz) 12.26 (s, 1H), 10.22 (s, Method(4-fluoro- Fluorobenzyl)-N³- 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.86 82phenyl)methanamine (5-cyclopropyl-1H- (t, J = 5.6 Hz, 1H), 7.36 (m, 2H),pyrazol-3-yl)-4- 7.17 (m, 2H), 6.90 (s, 1H), 6.24 (d, nitrobenzene-1,3-J = 9.6 Hz, 1H), 5.70 (s, 1H), 4.44 diamine (d, J = 5.6 Hz, 2H), 1.87(m, 1H), 0.94 (m, 2H), 0.69 (m 2H). MS: Calcd.: 367; Found: [M + H]⁺368. 29 (S)-N¹-[1-(4- MS: Calcd.: 399; Found: [M + H]⁺ Method (S)-1-(4-Fluorophenyl)ethyl]- 400. 83 fluoro- N³-(5-isopropoxy- phenyl)-1H-pyrazol-3-yl)-4- ethylamine nitrobenzene-1,3- diamine 30 (S)-N³-(5-(400 MHz) 12.28 (s, 1H), 10.18 (b, Method (S)-1- Cyclopropyl-1H- 1H),8.54 (s, 1H), 7.89 (d, J = 9.2 82 (pyridin-2- pyrazol-3-yl)-4- Hz, 1H),7.84 (d, J = 6.0 Hz, 1H), yl)- nitro-N¹-(1-(pyridin- 7.77 (m, 2H), 7.34(d, J = 8.0 Hz, ethylamine 2-yl)ethyl)benzene- 1H), 7.28 (m, 1H), 6.65(m, 1H), 1,3-diamine 6.24 (m, 1H), 5.60 (m, 1H), 4.60 (m, 1H), 1.89 (m,1H), 1.49 (d, J = 6.4 Hz, 3H), 0.97 (m, 2H), 0.73 (m 2H). MS: Calcd.:363; Found: [M + H]⁺ 365. 31 (R)-2-(4- (400 MHz) 12.22 (s, 1H), 10.15(s, Method (R)-2- Fluorophenyl)-2-(3- 1H), 7.87 (d, J = 9.6 Hz, 1H),7.75 84 amino-2-(4- (5-methyl-1H- (d, J = 6.0 Hz, 1H), 7.36 (m, 2H),fluorophenyl)ethanol pyrazol-3-ylamino)- 7.17 (m, 2H), 6.67 (b, 1H),6.28 4- (m, 1H), 5.53 (m, 1H), 5.06 (t, J = nitrophenylamino)ethanol 5.6Hz, 1H), 4.45 (m, 1H), 3.62 (t, J = 5.6 Hz, 2H), 2.23 (s, 3H). MS:Calcd.: 371; Found: [M + H]⁺ 372.

Method 32(S)-4-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitrobenzonitrile

A mixture of4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-fluoro-5-nitrobenzonitrile(Method 33; 3.0 g, 10.4 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (1.60g, 11.5 mmol), and DIEA (2.3 ml, 13.1 mmol) in n-BuOH (20 ml) was heatedin a sealed tube at 230° C. for 2 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=1:2) to give the title compound as a yellow solid (4.1 g,97%). NMR (400 MHz) 12.41 (s, 1H), 9.95 (s, 1H), 8.39 (s, 1H), 7.44 (m,2H), 7.38 (d, J=6.4 Hz, 1H), 7.13 (m, 2H), 6.95 (s, 1H), 5.68 (s, 1H),4.56 (m, 1H), 1.91 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 0.96 (m, 2H), 0.72(m 2H). MS: Calcd.: 406. Found: [M+H]⁺ 407.

Method 334-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-2-fluoro-5-nitrobenzonitrile

To a solution of 2,4-difluoro-5-nitrobenzonitrile (Method 34, 5.0 g, 27mmol) and DIEA (5.4 ml, 31 mmol) in THF (20 ml) was added dropwise asolution of 5-cyclopropyl-1H-pyrazol-3-amine (3.2 g, 26 mmol) in THF (5ml) at 0° C. After addition, the reaction mixture was stirred at 25° C.for 1 hour. The solvent was removed under reduced pressure and theresulted residue was purified by column chromatography(hexane:EtOAc=3:1) to give the title compound as a yellow solid (5.5 g,74%). NMR (400 MHz) 12.54 (s, 1H), 10.13 (s, 1H), 8.78 (d, J=7.2 Hz,1H), 8.10 (d, J=13.6 Hz, 1H), 6.02 (s, 1H), 1.91 (m, 1H), 0.97 (m, 2H),0.72 (m, 2H). MS: Calcd.: 287. Found: [M+H]⁺ 288.

Method 34 2,4-Difluoro-5-nitrobenzonitrile

Potassium nitrate (16.4 g, 147.4 mmol) was added to concentrated H₂SO₄(85 ml, 1582 mmol) at 0° C., followed by slow addition of2,4-difluorobenzonitrile (11.0 g, 79.1 mmol). The suspension was stirredat this temperature for an additional 4 hrs and quenched ice/water (800ml). The resulting solid was collected by filtration and dried to givethe title compound (13.8 g, 95%) as a white solid. NMR (400 MHz, CDCl₃)8.48 (m, 1H), 7.24 (m, 1H).

Method 35

Following a similar procedure to Method 32, the following compounds weresynthesized from4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-fluoro-5-nitrobenzonitrile(Method 33) and the appropriate amine.

Meth Product NMR/MS Amine 2 35 (R)-4-(5- (400 MHz) 12.40 (s, 1H), 9.95(s, 1H), (R)-2-amino-2-(4- Cyclopropyl-1H- 8.42 (s, 1H), 7.41 (m, 1H),7.12 (m, fluorophenyl)ethanol pyrazol-3-ylamino)- 4H), 6.93 (s, 1H),5.64 (s, 1H), 5.24 (t, 2-[1-(4- J = 5.2 Hz, 1H), 4.47 (m, 1H), 3.75 (m,fluorophenyl)-2- 1H), 3.69 (m, 1H), 1.91 (m, 1H), 0.99hydroxyethylamino]- (m, 2H), 0.71 (m, 2H). MS: Calcd.:5-nitrobenzonitrile 422; Found: [M + H]⁺ 423.

Method 36(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N¹-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine

A mixture of5-cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method85; 0.400 g, 1.43 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.209 g,1.50 mmol, and DIEA (0.373 ml, 2.14 mmol) in n-BuOH (3 ml) was heated ina sealed tube at 160° C. for 8 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=4:1) to give the title compound as an orange solid (0.40g, 70%). NMR (400 MHz) 11.95 (s, 1H), 8.74 (s, 1H), 7.72 (d, J=9.2 Hz,1H), 7.43 (t, J=7.0 Hz, 2H), 7.25 (d, J=6.4 Hz, 1H), 7.15 (t, J=8.8 Hz,2H), 6.26 (t, J=8.6 Hz, 1H), 5.63 (s, 1H), 4.78 (m, 1H), 1.84 (m, 1H),1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 399.Found: [M+H]⁺400.

Method 37

Following a similar procedure to Method 36, the following compound wassynthesized from5-cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method85) and the appropriate amine.

Meth Product NMR/MS Amine 2 37 (R)-2-[3-(5- (400 MHz) 11.95 (s, 1H),8.74 (s, 1H), 7.72 (R)-2-amino- Cyclopropyl-1H- (d, J = 9.6 Hz, 1H),7.42 (m, 2H), 7.15 (t, J = 2-(4- pyrazol-3-ylamino)- 8.8 Hz, 2H), 7.02(d, J = 4.4 Hz, 1H), 6.23 fluorophenyl)ethanol 2-fluoro-4- (t, J = 8.6Hz, 1H), 5.63 (s, 1H), 5.04 (t, J = nitrophenylamino]- 5.8 Hz, 1H), 4.65(m, 1H), 3.61-3.74 (m, 2-(4-fluorophenyl) 2H), 1.84 (m, 1H), 0.91 (m,2H), 0.66 (m, ethanol 2H). MS: Calcd.: 415; Found: [M + H]⁺ 416.

Method 38(S)—N¹-(5-Cyclopropyl-1H-pyrazol-3-yl)-4-fluoro-N³-[1-(4-fluorophenyl)ethyl]-6-nitrobenzene-1,3-diamine

A mixture of5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method86; 0.300 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.164 g,1.18 mmol), and DIEA (0.280 ml, 1.61 mmol) in n-BuOH (2 ml) was heatedin a sealed tube at 160° C. for 16 hrs. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane:EtOAc=3:1) to give the title compound as an orange solid (0.360g, 84%). NMR (400 MHz) 12.29 (s, 1H), 10.14 (s, 1H), 7.75 (d, J=12.8 Hz,1H), 7.63 (d, J=6.4 Hz, 1H), 7.41 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 7.00(d, J=8.0 Hz, 1H), 5.63 (s, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.52 (d,J=6.8 Hz, 3H), 0.98 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 399. Found:[M+H]⁺400.

Method 39

Following a similar procedure to Method 38, the following compounds weresynthesized from5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method86) and the appropriate amine.

Meth Product NMR/MS Amine 39 (R)-2-[5-(5- (400 MHz) 12.29 (s, 1H), 10.13(s, 1H), 7.77 (R)-2- Cyclopropyl-1H- (d, J = 12.8 Hz, 1H), 7.41 (m, J =6.4 Hz, 3H), amino-2-(4- pyrazol-3-ylamino)- 7.15 (t, J = 8.8 Hz, 2H),7.04 (d, J = 8.0 Hz, fluorophenyl)ethanol 2-fluoro-4- 1H), 5.60 (s, 1H),5.08 (t, J = 5.8 Hz, 1H), nitrophenylamino]- 4.45 (m, 1H), 3.62-3.80 (m,2H), 1.90 (m, 2-(4-fluorophenyl) 1H), 0.98 (m, 2H), 0.71 (m, 2H). MS:Calcd.: ethanol 415; Found: [M + H]⁺ 416.

Method 40(R)-2-[5-Amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methylpyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol

To a suspension of(R)-2-[4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methyl-5-nitropyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol(Method 1, 1.0 g, 2.4 mmol) and zinc dust (0.79 g, 12.0 mmol) in themixture of MeOH:THF (1:1, 70 ml) was slowly added saturated NH₄Clsolution (10 ml). After 3 hours, the reaction was treated with saturatedaqueous NH₄OAc solution (40 ml), and the resulting mixture was stirredfor 30 minutes. The reaction was then filtered through a plug of celitewith EtOAc (100 ml). The resulting aqueous layer was extracted withEtOAc (2×100 ml), dried, filtered, and concentrated to give (0.8 g,90%). MS: Calcd.: 383. Found: [M+H]⁺384.

Methods 41-46

Following a similar procedure to Method 40, the following compounds weresynthesized from a suitable nitro-pyrimidine.

Meth Compound NMR/MS SM 41 N⁴-(5-Cyclopropyl- 0.70 (m, 2H), 0.96 (m 2H),1.48 (d, J = 6 Hz, Method 1H-pyrazol-3-yl)-N²- 3H), 1.90 (m 1H), 5.05(t, J = 6 Hz, 1H), 6.20 2 [(1S)-1-(4- (s, 1H), 7.16 (m, 2H), 7.45 (m,2H), 8.83 (br s, fluorophenyl)ethyl]pyrimidine- 1H), 10.35 (br s, 1H).MS: Calcd.: 353; Found: 2,4,5-triamine [M + H]⁺ 354.21 42(2R)-2-({5-Amino-4- 0.65 (m, 2H), 0.90 (m 2H), 1.80 (m, 1H), 3.56 Method[(5-cyclopropyl-1H- (m, 2H), 4.80 (m, 1H), 6.50 (s, 1H), 7.10 (m, 3pyrazol-3- 2H), 7.36 (m, 2H), 8.25 (br s, 1H). MS: Calcd.:yl)amino]pyrimidin- 369; Found: [M + H]⁺ 370.22 2-yl}amino)-2-(4-fluorophenyl)ethanol 43 N⁴-(5-Cyclopropyl- MS: Calcd.: 339; Found: [M +H]⁺ 340.19 Method 1H-pyrazol-3-yl)-N²- 4 (4-fluorobenzyl)pyrimidine-2,4,5- triamine 44 N⁴-(5-Cyclopropyl- MS: Calcd.: 353; Found:[M + H]⁺ 354.21 Method 1H-pyrazol-3-yl)-N²- 5 [(1R)-1-(4-fluorophenyl)ethyl]pyrimidine- 2,4,5-triamine 45 (R)-2-(5-Amino-4-(5-MS: Calcd.: 343; Found: [M + H]⁺ 344 Method methyl-1H-pyrazol-3- 6ylamino)pyrimidin-2- ylamino)-2-(4- fluorophenyl)ethanol 46(S)-N²-(1-(4- MS: Calcd.: 371; Found: [M + H]⁺ 372 MethodFluorophenyl)ethyl)- 7 N⁴-(5-isopropoxy- 1H-pyrazol-3-yl)pyrimidin-2,4,5- triamine

Method 47 (S)-Ethyl5-amino-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]pyrimidine-4-carboxylate

To a suspension of (S)-ethyl6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitropyrimidine-4-carboxylate(Method 10; 0.7 g, 1.5 mmol) and zinc dust (0.5 g, 7.7 mmol) in EtOH:THF(1:1, 20 ml) was slowly added saturated aqueous NH₄Cl solution (3 ml).After 1 hour, the reaction mixture was cooled to 0° C., to which wasadded saturated NH₄OAc solution (10 ml). The resulting mixture wasallowed to stir for 10 minutes at 0° C. and then filtered through a plugof celite with EtOAc (100 ml). The resulting aqueous layer was extractedwith EtOAc (2×100 ml), dried, filtered, and concentrated to give thetitle compound (0.60 g, 92%) which was used without furtherpurification.

Method 48(S)—N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]pyridine-2,3,6-triamine

To a suspension of(S)—N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-[1-(4-fluorophenyl)ethyl]-3-nitropyridine-2,6-diamine(Method 12; 0.26 g, 0.68 mmol) and zinc dust (0.223 g, 3.41 mmol) inMeOH:THF (1:1, 12 ml) was slowly added saturated ammonium chloridesolution (1.5 ml). The reaction mixture was stirred at 25° C. for 1hour, to which was then added saturated ammonium acetate solution (5ml). The resulting mixture was stirred for another 30 minutes. Zn dustwas removed by filtration and washed with EtOAc (20 ml). The organiclayer was separated, washed with brine (10 ml), dried over Na₂SO₄, andconcentrated. The title compound was used directly for the next stepwithout further purification.

Methods 49-61

Following a similar procedure to Method 48, the following compounds weresynthesized from a suitable nitro-pyridine.

Meth Compound NMR/MS SM 49 N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-(4- MS:Calcd.: 338; Method fluorobenzyl)pyridine-2,3,6-triamine Found: [M + H]⁺339 13 50 (2R)-2-({5-Amino-6-[(5-cyclopropyl-1H- MS: Calcd.: 368; Methodpyrazol-3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺ 369 14fluorophenyl)ethanol 51 2-({5-Amino-6-[(5-cyclopropyl-1H-pyrazol-3- MS:Calcd.: 398; Method yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺399 15 fluorophenyl)propane-1,3-diol 525-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)- MS: Calcd.: 386; MethodN⁶-[(1S)-1-(4-fluorophenyl)ethyl]pyridine- Found: [M + H]⁺ 387 162,3,6-triamine 53 5-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)- MS:Calcd.: 372; Method N⁶-(4-fluorobenzyl)pyridine-2,3,6-triamine Found:[M + H]⁺ 373 17 54 (2R)-2-({5-Amino-3-chloro-6-[(5-cyclopropyl- MS:Calcd.: 402; Method 1H-pyrazol-3-yl)amino]pyridin-2-yl}amino)-2- Found:[M + H]⁺ 403 18 (4-fluorophenyl)ethanol 55(2R)-2-({5-Amino-3-chloro-6-[(5-methyl-1H- MS: Calcd.: 376; Methodpyrazol-3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺ 377 19fluorophenyl)ethanol 56 (S)-N²-(5-Isopropoxy-1H-pyrazol-3-yl)-N⁶-(1- MS:Calcd.: 353; Method (pyridin-2-yl)ethyl)pyridine-2,3,6-triamine Found:[M + H]⁺ 354 20 57 (S)-N⁶-(1-(4-Fluorophenyl)ethyl)-N²-(5- MS: Calcd.:370; Method isopropoxy-1H-pyrazol-3-yl)-pyridine-2,3,6- Found: [M + H]⁺371 21 triamine 58 (R)-2-(5-Amino-6-(5-isopropoxy-1H-pyrazol-3- MS:Calcd.: 386; Method ylamino)pyridin-2-ylamino)-2-(4- Found: [M + H]⁺387. 22 fluorophenyl)ethanol 59(S)-5-Chloro-N⁶-(1-(4-fluorophenyl)ethyl)-N²- MS: Calcd.: 404; Method5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,3,6- Found: [M + H]⁺ 405. 23triamine 60 (S)-N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1- MS: Calcd.:335; Method (pyridin-2-yl)ethyl)pyridine-2,3,6-triamine Found: [M + H]⁺336. 24 61 (R)-2-(5-Amino-6-(5-methyl-1H-pyrazol-3- MS: Calcd.: 342;Method ylamino)pyridin-2-ylamino)-2-(4- Found: [M + H]⁺ 343. 25fluorophenyl)ethanol

Method 62(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine

To a suspension of(S)—N³-(5-cyclopropyl-1H-pyrazol-3-yl)-N¹-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine(Method 26; 0.37 g, 0.97 mmol) and Zinc dust (0.317 g, 4.85 mmol) inMeOH:THF (1:1, 24 ml) was slowly added saturated ammonium chloride (3.0ml). The reaction mixture was stirred at 25° C. for 1 hr, to which wasthen added saturated ammonium acetate solution (5 ml). The resultingmixture was stirred for another 30 min. Zn dust was removed byfiltration and washed with EtOAc (20 ml). The organic layer wasseparated, washed with brine (10 ml), dried over Na₂SO₄, andconcentrated. The crude product was used directly for the next stepwithout further purification. MS: Calcd: 351. Found: [M+H]⁺ 352.

Methods 63-68

Following a similar procedure to Method 62, the following compounds weresynthesized from a suitable nitrobenzene by reduction.

Meth Compound NMR/MS SM 63(2R)-2-({4-Amino-3-[(5-cyclopropyl-1H-pyrazol- MS: Calcd: 367; Method3-yl)amino]phenyl}amino)-2-(4- Found: [M + H]⁺ 368 27fluorophenyl)ethanol 64 N²-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁴-(4- MS:Calcd: 337; Method fluorobenzyl)benzene-1,2,4-triamine Found: [M + H]⁺338 28 65 N⁴-[(1S)-1-(4-Fluorophenyl)ethyl]-N²-(5- MS: Calcd: 369;Method isopropoxy-1H-pyrazol-3-yl)benzene-1,2,4- Found: [M + H]⁺ 370 29triamine 67 (S)-N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-N¹-(1- MS: Calcd:334; Method (pyridin-2-yl)ethyl)benzene-1,3,4-triamine Found: [M + H]⁺30 335. 68 (R)-2-(4-Amino-3-(5-methyl-1H-pyrazol-3- MS: Calcd: 341;Method ylamino)phenylamino)-2-(4-fluorophenyl)ethanol Found: [M + H]⁺ 31342.

Method 69(S)-5-Amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]benzonitrile

To a suspension of(S)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitrobenzonitrile(Method 32; 4.10 g, 10.1 mmol) and zinc dust (3.30 g, 50.4 mmol) inMeOH:THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40ml). The reaction mixture was stirred at 25° C. for 1 hr, to which wasadded saturated ammonium acetate solution (50 ml). The resulting mixturewas stirred for another 30 min. The Zn dust was removed by filtrationand washed with EtOAc (200 ml). The organic layer was separated, washedwith brine (100 ml), dried over Na₂SO₄, and concentrated. The titlecompound was used directly for the next step without furtherpurification. MS: Calcd: 376. Found: [M+H]⁺ 377.

Method 70

Following a similar procedure to Method 69, the following compounds weresynthesized from a suitable nitrobenzene.

Meth Compound NMR/MS SM 70 5-Amino-4-[(5-cyclopropyl- MS: Calcd: 392;Method 1H-pyrazol-3-yl)amino]-2- Found: [M + H]⁺ 35{[(1R)-1-(4-fluorophenyl)-2- 393 hydroxyethyl]amino}benzonitrile

Method 71(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine

To a suspension of(S)—N³-(5-cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N¹-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine(Method 36; 0.40 g, 1.00 mmol) and zinc dust (0.327 g, 5.00 mmol) inMeOH:THF (1:1, 10 ml) was slowly added saturated ammonium chloride (4ml). The mixture was stirred at 25° C. for 2 hours, to which was thenadded saturated ammonium acetate solution (5 ml). The resulting mixturewas stirred for another 30 minutes. The Zn dust was removed byfiltration and washed with EtOAc (15 ml). The organic layer wasseparated, washed with brine, dried over Na₂SO₄, and concentrated. Thetitle compound was used directly for the next step without furtherpurification.

Method 72

Following a similar procedure to Method 71, the following compound wassynthesized from a suitable nitrobenzene. The compound was used directlyfor the next step without further purification.

Meth Compound SM 72 (2R)-2-({4-Amino-3-[(5-cyclopropyl-1H-pyrazol-Method 3-yl)amino]-2-fluorophenyl}amino)-2-(4- 37 fluorophenyl)ethanol

Method 73(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-N¹-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine

To a suspension of(S)—N¹-(5-cyclopropyl-1H-pyrazol-3-yl)-4-fluoro-N³-[1-(4-fluorophenyl)ethyl]-6-nitrobenzene-1,3-diamine(Method 38; 0.33 g, 0.826 mmol) and Zinc dust (0.270 g, 4.13 mmol) inMeOH:THF (1:1, 10 ml) was slowly added saturated ammonium chloride (4ml). The mixture was stirred at 25° C. for 2 hrs, to which was addedsaturated ammonium acetate solution (5 ml). The resulting mixture wasstirred for another 30 min. The Zn dust was removed by filtration andwashed with EtOAc (15 ml). The organic layer was separated and driedover Na₂SO₄. After removal of solvent, the title compound was useddirectly for the next step without further purification.

Method 74

Following a similar procedure to Method 73, the following compounds weresynthesized from a suitable nitrobenzene. The compound was used directlyfor the next step without further purification.

Meth Compound SM 74 (2R)-2-({4-Amino-5-[(5-cyclopropyl-1H-pyrazol-Method 3-yl)amino]-2-fluorophenyl}amino)-2-(4- 39 fluorophenyl)ethanol

Method 752-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-nitropyrimidin-4-amine

A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.8 g, 14.0 mmol) inn-BuOH (25 ml) was slowly added to the n-BuOH (60 ml) solution of2,4-dichloro-6-methyl-5-nitropyrimidine (3.0 g, 14.0 mmol) and DIEA (2.4g, 19.0 mmol). After 5 minutes, the reaction was diluted with hexane(100 ml). The resulting precipitate was collected by filtration to yieldthe title compound (4.1 g, 96%). MS: Calcd.: 294. Found: [M+H]⁺ 295.

Method 762-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (3.0 g, 15 mmol) andDIEA (2.4 g, 18.5 mmol) in n-BuOH (30 ml) was slowly added5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16.2 mmol) at 25° C. Theresulting solution was stirred at 25° C. for 5 minutes and concentratedto dryness to give the title compound (3.1 g). NMR (CDCl₃) 0.80 (m, 2H),1.05 (m, 2H), 6.60 (s, 1H), 9.20 (s, 1H), 9.70 (br s, 1H), 10.40 (br s,1H).

Method 776-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (0.67 g, 3.2 mmol) andDIEA (0.46 ml, 2.65 mmol) in EtOH (20 ml) was added a5-cyclopropyl-1H-pyrazol-3-amine (0.26 g, 2.12 mmol) solution in EtOH (5ml) dropwise at 0° C. After addition, the reaction mixture was stirredat 25° C. for 24 hours. The solvent was removed under reduced pressureand the resulted residue was purified by column chromatography(hexane:EtOAc=5:1) to give the title compound as a yellow solid (0.58 g,98%). NMR (400 MHz) 12.36 (s, 1H), 10.20 (s, 1H), 8.54 (d, J=8.4 Hz,1H), 7.01 (d, J=8.4 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 1.94 (m, 1H), 0.96(m, 2H), 0.71 (m, 2H). MS: Calcd.: 279. Found: [M+H]⁺ 280.

Method 78

Following a similar procedure to Method 77, the following compound wassynthesized from a nitropyridine by reacting it with the appropriateamine.

Meth Product NMR/MS Amine 78 6-Chloro-N-(5- (400 MHz) 12.36 (s, 1H),10.24 (s, 1H), 5-methyl-1H- methyl-1H-pyrazol-3- 8.55 (d, J = 8.8 Hz,1H), 7.02 (d, J = 8.8 pyrazol-3-amine yl)-3-nitropyridin-2- Hz, 1H),6.48 (s, 1H), 2.27 (s, 3H). MS: amine Calcd.: 253; Found: [M + H]⁺ 254.

Method 795,6-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridine-2-amine

To a solution of 2,3,6-trichloro-5-nitropyridine (1.62 g, 7.10 mmol) andDIEA (1.24 ml, 7.1 mmol) in THF (25 ml) was added dropwise a solution of5-cyclopropyl-1H-pyrazol-3-amine (0.70 g, 5.68 mmol) in THF (5 ml) at 0°C. After addition, the reaction mixture was stirred at 25° C. for 24hours. The solvent was removed under reduced pressure and the resultedresidue was purified by column chromatography (hexane:EtOAc=1.5:1) togive the title compound as a yellow solid (0.83 g, 47%). NMR (400 MHz)12.39 (s, 1H), 10.12 (s, 1H), 8.77 (d, J=1.2 Hz, 1H), 6.35 (s, 1H), 1.95(m, 1H), 0.96 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 313. Found: [M+H]⁺ 314.

Methods 80-81

Following a similar procedure to Method 79, the following compounds weresynthesized from a 2,3,6-trichloro-5-nitropyridine by reacting it withthe appropriate amine.

Meth Product NMR/MS Amine 80 (R)-2-(3,6-Dichloro-5- (400 MHz) 8.46 (s,1H), 8.22 (d, J = (R)-2-amino-2- nitropyridin-2- 8.0 Hz, 1H), 7.45 (m,2H), 7.16 (m, (4-fluorophenyl) ylamino)-2-(4- 2H), 5.22 (m, 1H), 5.05(t, J = 6.0 Hz, ethanol fluorophenyl) ethanol 1H), 3.87 (m, 1H), 3.72(m, 1H) 81 5,6-Chloro-N-(5- (400 MHz) 12.26 and 11.64 (s, 1H),5-isopropoxy- isopropoxy-1H- 10.42 and 10.04 (s, 1H), 8.81 and 8.771H-pyrazol-3-amine pyrazol-3-yl)-3- (s, 1H), 6.02 and 5.94 (s, 1H), 4.70nitropyridine-2-amine and 4.48 (m, 1H), 1.32 and 1.27 (d, J = 6.0 Hz,6H). MS: Calcd.: 331; Found: [M + H]⁺ 332.

Method 82 5-Cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazol-3-amine

To a solution of 2,4-difluoro-1-nitrobenzene (1.76 g, 11.1 mmol) andDIEA (1.93 ml, 11.1 mmol) in THF (20 ml) was added dropwise a solutionof 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.39 mmol) in THF (5 ml) at25° C. After addition, the reaction mixture was stirred at 80° C. for 48hours. The solvent was removed under reduced pressure and the resultedresidue was purified by column chromatography (hexane:DCM:EtOAc=2:1:1)to give the title compound as a yellow solid (0.62 g, 32%). NMR (400MHz) 12.37 (s, 1H), 9.83 (s, 1H), 8.25 (m, 1H), 7.98 (d, J=11.2 Hz, 1H),6.75 (m, 1H), 5.95 (s, 1H), 1.90 (m, 1H), 0.96 (m, 2H), 0.72 (m, 2H).

Methods 83-84

Following a similar procedure to Method 82 the following compounds weresynthesized from 2,4-difluoro-1-nitrobenzene and the appropriate amine.

Meth Product NMR/MS Amine 83 N-(5-Fluoro-2- MS: Calcd.: 280; Found: [M +H]⁺ 281 5-isopropoxyl- nitrophenyl)-5- 1H-pyrazol-3- isopropoxy-1H-amine pyrazol-3-amine 84 5-Methyl-N-(5- (400 MHz) 12.34 (s, 1H), 9.85(s, 1H), 8.25 5-methyl-1H- fluoro-2- (m, 1H), 7.99 (dd, J = 12.8 and 2.8Hz, 1H), pyrazol-3- nitrophenyl)-1H- 6.75 (m, 1H), 6.03 (d, J = 2.0 Hz,1H), 2.24 amine pyrazol-3-amine (s, 3H). MS: Calcd.: 236; Found: [M +H]⁺ 237.

Method 855-Cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-1H-pyrazol-3-amine

To a solution of 1,2,3-trifluoro-4-nitrobenzene (3.2 g, 18 mmol) andDIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solutionof 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0°C. After addition, the reaction mixture was stirred at 25° C. for 21hours. The solvent was removed under reduced pressure and the resultedresidue was purified by column chromatography (hexane:EtOAc=5:2).Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave thetitle compound as red crystals (1.5 g, 33%). NMR (400 MHz) 11.90 (s,1H), 8.78 (s, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.08 (q, J=8.7 Hz, 1H), 5.60(s, 1H), 1.83 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 280.Found: [M+H]⁺281.

Method 865-Cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-1H-pyrazol-3-amine

To a solution of 1,2,4-trifluoro-5-nitrobenzene (3.0 g, 18 mmol) andDIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solutionof 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0°C. After addition, the reaction mixture was stirred at 25° C. for 20hrs. It was then heated to 40° C. for 40 hrs. The solvent was removedunder reduced pressure and the resulted residue was purified by columnchromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml)and hexanes (˜100 ml) gave the title compound as red crystals (0.8 g,18%). NMR (400 MHz) 12.36 (s, 1H), 9.79 (s, 1H), 8.27 (m, 2H), 5.93 (s,1H), 1.90 (m, 1H), 0.93 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 280. Found:[M+H]⁺281.

Method 872-Chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (0.41 g, 2.1 mmol) andDIEA (0.31 ml, 1.8 mmol) in THF (10 ml) was added5-isopropoxy-1H-pyrazol-3-amine (0.20 g, 1.4 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 hour. The solvent was removed underreduced pressure and the resulted residue was purified by columnchromatography (DCM:EtOAc=2.5:1) to give the title compound as a yellowsolid (0.19 g, 45%). MS: Calcd.: 298. Found: [M+H]⁺299.

Method 88(S)—N⁴-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,4,5-triamine

To a suspension of(S)—N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)-5-nitropyridine-2,4-diamine(Method 89, 0.15 g, 0.40 mmol) and zinc dust (0.13 g, 2.0 mmol) inMeOH-THF (1:1, 16 ml) was slowly added saturated ammonium chloridesolution (2 ml). The reaction mixture was stirred at 25° C. for 1 hour,to which was added saturated ammonium acetate solution (5 ml). Theresulting mixture was stirred for another 30 min. Zn dust was removed byfiltration and washed with EtOAc (20 ml). The organic layer wasseparated, washed with brine (10 ml), dried over Na₂SO₄, andconcentrated. The crude product was used directly for the next stepwithout further purification. MS: Calcd.: 352. Found: [M+H]⁺ 353.

Method 89(S)—N⁴-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)-5-nitropyridine-2,4-diamine

A mixture of2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine(Method 90, 0.15 g, 0.54 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine(0.093 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) washeated in a sealed tube at 180° C. for 32 hours. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (hexane-EtOAc=1:1) to give the title compound as a yellowsolid (0.168 g, 82%). ¹H NMR (400 MHz) 12.37 (s, 1H), 9.59 (b, 1H), 8.83(s, 1H), 8.20 (b, 1H), 7.37 (m, 2H), 7.13 (m, 2H), 6.69 (b, 1H), 5.88(b, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 0.97 (m,2H), 0.71 (m 2H). MS: Calcd.: 382. Found: [M+H]⁺ 383.

Method 902-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine

To a solution of 2,4-dichloro-5-nitropyridine (Method 91, 0.42 g, 2.18mmol) and DIEA (0.46 ml, 2.61 mmol) in THF (10 ml) was added a5-cyclopropyl-1H-pyrazol-3-amine (0.31 g, 2.50 mmol) solution in THF (5ml) drop wise at 0° C. After addition, the reaction mixture was stirredat 25° C. for 17 hours. The solvent was removed under reduced pressureand the resulted residue was purified by column chromatography(hexane:EtOAc=3:1) to give the title compound as a yellow solid (0.54 g,89%). ¹H NMR (400 MHz) 12.55 (s, 1H), 9.95 (s, 1H), 8.97 (s, 1H), 8.09(s, 1H), 6.02 (d, J=2.0 Hz, 1H), 1.93 (m, 1H), 0.97 (m, 2H), 0.71 (m,2H). MS: Calcd.: 279. Found: [M+H]⁺ 280.

Method 91 2,4-Dichloro-5-nitropyridine

To 4-chloro-5-nitropyridine-2-amine (Method 92, 4.40 g, 21.0 mmol) inconcentrated HCl (70 ml) was added sodium nitrite (4.36 g, 63.1 mmol)potion wise at 0-5° C. After 1 hour at 0-5° C., the reaction was warmedto room temperature and stirred for 50 hours. Ice (100 g) was added andthe mixture was extracted with ether (2×50 ml) and dried over sodiumsulfate. The solvent was removed under reduced pressure and the resultedresidue was purified by column chromatography (hexane-DCM=1:5) to givethe title compound as a white solid (1.47 g, 33%). ¹H NMR (400 MHz) 9.18(s, 1H), 8.22 (s, 1H).

Method 92 4-Chloro-5-nitropyridine-2-amine

To 4-chloro-3-nitropyridine (10.0 g, 63.1 mmol) in 500 ml of liquidammonium was added potassium permanganate (19.9 g, 126.1 mmol). Thereaction was stirred at this temperature (−33° C.) for 5 hours thenslowly warmed to room temperature. After evaporation of ammonia, water(1 L) was added. The solid formed was collected by filtration and washedwith water (2 L). The solid was extracted with 1:1=DCM:EtOAc (5×500 ml).The solvent was removed and the resulting solid was recrystallized fromEtOAc (400 ml) to give the title compound as a yellow solid (4.4 g,33%). ¹H NMR (400 MHz) 8.88 (s, 1H), 7.65 (b, 2H), 6.62 (s, 1H).

Method 93(R)-2-(5-Amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

To a suspension of(R)-2-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 94, 0.14 g, 0.36 mmol) and zinc dust (0.12 g, 1.78 mmol) inMeOH-THF (1:1, 16 ml) was slowly added saturated ammonium chloride (2.0ml). The reaction mixture was stirred at 25° C. for 1 hour, to which wasthen added saturated ammonium acetate solution (5 ml). The resultingmixture was stirred for another 30 minutes. The Zn dust was removed byfiltration and washed with EtOAc (20 ml). The organic layer wasseparated, washed with brine (10 ml), dried over sodium sulfate, andconcentrated. The crude product was used directly for the next stepwithout further purification. MS: Calcd.: 368. Found: [M+H]⁺ 369.

Method 94(R)-2-(4-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

A mixture of2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine(Method 90, 0.15 g, 0.54 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol(0.10 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) washeated in a sealed tube at 195° C. for 52 hours. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc) to give the title compound as a yellow solid(0.15 g, 72%). ¹H NMR (400 MHz) 12.38 (s, 1H), 9.59 (b, 1H), 8.83 (s,1H), 8.16 (b, 1H), 7.37 (m, 2H), 7.13 (m, 2H), 6.75 (b, 1H), 5.92 (b,1H), 5.25 (b, 1H), 4.98 (m, 1H), 3.61 (t, J=6.4 Hz, 2H), 1.92 (m, 1H),0.97 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 398. Found: [M+H]⁺ 399.

Method 956-Chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine

To a solution of 2,6-dichloro-3-nitropyridine (1.0 g, 5.3 mmol) and DIEA(0.77 ml, 4.4 mmol) in THF (20 ml) was added5-isopropoxy-1H-pyrazol-3-amine (0.50 g, 3.5 mmol). The reaction mixturewas stirred at 25° C. for 3 days and 60° C. for 1 hour. The solvent wasremoved under reduced pressure and the resulted residue was purified bycolumn chromatography (hexane-EtOAc=3:1) to give the title compound as ayellow solid (0.62 g, 59%). ¹H NMR (400 MHz) 12.25 and 11.66 (s, 1H),10.46 and 10.13 (s, 1H), 8.56 (m, 1H), 7.11 and 7.02 (d, J=8.4 Hz, 1H),6.08 and 5.97 (s, 1H), 4.70 and 4.48 (m, 1H), 1.32 and 1.27 (d, J=6.0Hz, 6H). MS: Calcd.: 297. Found: [M+H]⁺ 298.

Method 96(S)-2-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzonitrile

To a suspension of(S)-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile(Method 97, 4.20 g, 10.0 mmol) and zinc dust (3.40 g, 52 mmol) inMeOH-THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40ml). The reaction mixture was stirred at 25° C. for 1 hour, to which wasthen added saturated ammonium acetate solution (50 ml). The resultingmixture was stirred for another 30 minutes. Zn dust was removed byfiltration and washed with EtOAc (200 ml). The organic layer wasseparated, washed with brine (100 ml), dried over sodium sulfate, andconcentrated. The crude product was used directly for the next stepwithout further purification. MS: Calcd: 376. Found: [M+H]⁺ 377.

Method 97(S)-3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile

A mixture of3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-nitrobenzonitrile(Method 98, 3.50 g, 12.2 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (1.87g, 13.4 mmol), and DIEA (2.6 ml, 14.6 mmol) in n-BuOH (20 ml) was heatedin a sealed tube at 230° C. for 2 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:2) to give the title compound as a yellow solid (4.4 g,89%). ¹H NMR (400 MHz) 12.38 (s, 1H), 10.12 (b, 1H), 8.07 (d, J=6.4 Hz,1H), 7.34 (m, 2H), 7.16 (m, 2H), 6.89 (b, 1H), 6.77 (s, 1H), 5.63 (m,1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.97 (m, 2H),0.70 (m 2H). MS: Calcd.: 406. Found: [M+H]⁺ 407.

Method 983-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-nitrobenzonitrile

To a solution of 3,5-difluoro-2-nitrobenzonitrile (Method 99, 5.8 g,31.5 mmol) and DIEA (5.5 ml, 31.5 mmol) in THF (50 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (4.66 g, 37.8 mmol)in THF (5 ml) at 0° C. After addition, the reaction mixture was stirredat 25° C. for 20 hours. The solvent was removed under reduced pressureand the resulted residue was purified by column chromatography(DCM-EtOAc=10:1) to give the title compound as a yellow solid (5.5 g,61%). ¹H NMR (400 MHz) 12.43 (s, 1H), 9.70 (s, 1H), 8.22 (dd, J=11.2 and2.0 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H), 5.92 (s, 1H), 1.90 (m, 1H), 0.95(m, 2H), 0.71 (m, 2H). MS: Calcd.: 287. Found: [M+H]⁺ 288.

Method 99 3,5-Difluoro-2-nitrobenzonitrile

Potassium nitrate (6.56 g, 64.8 mmol) was added to concentrated H₂SO₄(33.7 ml, 633 mmol) at 0° C., followed by slow addition of3,5-difluorobenzonitrile (4.4 g, 31.6 mmol). The suspension was stirredat this temperature for an additional 3 hours and quenched with icewater (500 ml). The resulting solid was collected by filtration anddried to give the title compound (5.55 g, 95%) as a white solid. ¹H NMR(400 MHz, CDCl₃) 7.43 (m, 1H), 7.35 (m, 1H).

Method 100(S)-2-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzamide

To a suspension of(S)-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile(Method 97; 4.20 g, 10.0 mmol) and zinc dust (3.40 g, 52 mmol) inMeOH-THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40ml). The reaction mixture was stirred at 25° C. for 1 hour, to which wasthen added saturated ammonium acetate solution (50 ml). The resultingmixture was stirred for another 30 minutes. Zn dust was removed byfiltration and washed with EtOAc (200 ml). The organic layer wasseparated, washed with brine (100 ml), dried over sodium sulfate, andconcentrated. The crude product was used directly for the next stepwithout further purification. MS: Calcd: 394. Found: [M+H]⁺ 395.

Method 101(S)—N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluoro-N¹-(1-(4-fluorophenyl)ethyl)benzene-1,3,4-triamine

A solution of saturated ammonium chloride (4 ml) was added slowly to asuspension of(S)—N¹-(5-cyclopropyl-1H-pyrazol-3-yl)-2,4-difluoro-N³-(1-(4-fluorophenyl)ethyl)-6-nitrobenzene-1,3-diamine(Method 102, 0.30 g, 0.719 mmol) and zinc dust (0.235 g, 3.59 mmol) inMeOH/THF (10 ml, 1:1). The mixture was stirred at 25° C. for 2 hours.Saturated ammonium acetate solution (5 ml) was added and the mixture wasstirred for another 30 minutes. Zn dust was removed by filtration andthe cake was washed with EtOAc (15 ml). The organic layer was separatedand dried over sodium sulfate. After removal of solvent, the product wasused directly for the next step without further purification.

Method 102(S)—N¹-(5-Cyclopropyl-1H-pyrazol-3-yl)-2,4-difluoro-N³-(1-(4-fluorophenyl)ethyl)-6-nitrobenzene-1,3-diamine

A mixture of5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine(Method 103, 0.300 g, 1.01 mmol), (S)-1-(4-fluorophenyl)ethylamine(0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) washeated in a sealed tube placed in an oil bath set at 135° C. for 8hours. The solvent was removed under reduced pressure and the residuewas purified by chromatography (hexane-EtOAc=3:1) to give the titlecompound as an orange solid (0.30 g, 71%). ¹H NMR (400 MHz) 11.89 (s,1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6 Hz), 7.35 (m, 2H), 7.14 (t, J=8.8Hz, 2H), 6.81 (d, 1H, 7.6 Hz), 5.39 (s, 1H), 5.00 (m, 1H), 1.80 (m, 1H),1.49 (d, J=6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417.Found: [M+H]⁺ 418.

Method 1035-Cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine

To 1,2,3,4-tetrafluoro-5-nitrobenzene (3.0 g, 15.4 mmol) and DIEA (3.7ml, 21.0 mmol) in dry THF (20 ml) was added5-cyclopropyl-1H-pyrazol-3-amine (1.7 g, 14.0 mmol) in THF (5 ml) dropwise at 0° C. After addition, the reaction mixture was stirred at 25° C.for 16 hours. The solvent was removed under reduced pressure and theresulted residue was purified by column chromatography(hexane-EtOAc=4:1). This was recrystallized from Et₂O (20 ml) andhexanes (˜150 ml) to give the title compound as red crystals (0.650 g,16%). ¹H NMR (400 MHz) 11.84 (s, 1H), 8.67 (s, 1H), 8.06 (m, 1H), 5.57(s, 1H), 1.82 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 298.Found: [M+H]⁺ 299.

Method 104(R)-2-(4-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluorophenylamino)-2-(4-fluorophenyl)ethanol

A solution of saturated ammonium chloride (4 ml) was added slowly to asuspension(R)-2-(3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluoro-4-nitrophenylamino)-2-(4-fluorophenyl)ethanol(Method 105, 0.250 g, 0.577 mmol) and zinc dust (0.189 g, 2.88 mmol) inMeOH/THF (10 ml, 1:1). The mixture was stirred at 25° C. for 5 minutes.Saturated ammonium acetate solution (5 ml) was added and the mixture wasstirred for another 30 minutes. Zn dust was removed by filtration andthe cake was washed with EtOAc (15 ml). The organic layer was separatedand dried over sodium sulfate. After removal of solvent, the product wasused directly for the next step without further purification.

Method 105(R)-2-(3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluoro-4-nitrophenylamino)-2-(4-fluorophenyl)ethanol

A mixture of5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine(Method 103, 0.300 g, 1.01 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol(0.172 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) washeated in a sealed tube placed in an oil bath set at 135° C. for 8hours. The solvent was removed under reduced pressure and the residuewas purified by chromatography (hexane-EtOAc=1:1) to give the titlecompound as an orange solid (0.25 g, 57%). ¹H NMR (400 MHz) 11.88 (s,1H), 8.57 (s, 1H), 7.70 (d, J=13.2 Hz, 1H), 7.34 (m, 2H), 7.15 (t, J=8.8Hz, 2H), 6.61 (b, 1H), 5.38 (s, 1H), 5.07 (t, J=5.6 Hz, 1H), 4.88 (m,1H), 3.62-3.71 (m, 2H), 1.80 (m, 1H), 0.90 (m, 2H), 0.61 (m, 2H). MS:Calcd.: 433. Found: [M+H]⁺ 434.

Utility

The compounds of the present invention have utility for the treatment ofcancer by inhibiting the tyrosine kinases, particularly the Trks andmore particularly Trk A and B. Methods of treatment target tyrosinekinase activity, particularly the Trk activity and more particularly TrkA and B activity, which is involved in a variety of cancer relatedprocesses. Thus, inhibitors of tyrosine kinase, particularly the Trksand more particularly Trk A and B, are expected to be active againstneoplastic disease such as carcinoma of the breast, ovary, lung, colon,prostate or other tissues, as well as leukemias and lymphomas, tumoursof the central and peripheral nervous system, and other tumour typessuch as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinaseinhibitors, particularly the Trk inhibitors and more particularly Trk Aand B inhibitors are also expected to be useful for the treatment otherproliferative diseases including but not limited to autoimmune,inflammatory, neurological, and cardiovascular diseases.

In addition, the compounds of the invention are expected to be of valuein the treatment or prophylaxis of cancers selected with up regulated ofconstitutively activated Trk kinases, including but not limited to,oncogenic rearrangements leading to ETV6-TrkC fusions, TRP-TrkA fusionsproteins, AML-ETO (t8; 21), autocrine or paracrine signalling leading toelevated serum levels of NGF, BDNF, neurotropins or tumours withconstitutively active Trk associated with disease aggressiveness, tumourgrowth and proliferation or survival signalling.

Compounds of the present invention have been shown to inhibit tyrosinekinases, particularly the Trks and more particularly Trk A and B, asdetermined by the Trk A Assay described herein.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit tyrosine kinases, particularly the Trks and more particularlyTrk A and B. These would be provided in commercial kits comprising acompound of this invention

Trk A Assay Format

Trk A kinase activity was measured for its ability to phosphorylatesynthetic tyrosine residues within a generic polypeptide substrate usingan Amplified Luminescent Proximity Assay (Alphascreen) technology(PerkinElmer, 549 Albany Street, Boston, Mass.).

To measure Trk A kinase activity, the intracellular domain of aHIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-ProtPrimary Accession Number P04629) was expressed in SF9 cells and purifiedusing standard nickel column chromatography. After incubation of thekinase with a biotinylated substrate and adenosine triphosphate (ATP)for 20 minutes at room temperature, the kinase reaction was stopped bythe addition of 30 mM ethylenediaminetetraacetic acid (EDTA). Thereaction was performed in 384 well microtitre plates and the reactionproducts were detected with the addition of strepavidin coated DonorBeads and phosphotyrosine-specific antibodies coated Acceptor Beadsusing the EnVision Multilabel Plate Reader after an overnight incubationat room temperature.

Peptide substrate PolyEY-biotin (PGT-bio.) ATP Km 70 μM Assay conditions0.838 ng/ml Trk A, 9 mM HEPES, 45 μg/ml BSA, 10 mM MnCl₂, 5 nM PGT-bio,0.01% Triton ® X-100, 70 μM ATP Incubation 20 minutes, room temperatureTermination/Detection 6.3 mM HEPES, 30 mM EDTA, 525 μg/ml conditionsBSA, 40 mM NaCl, 0.007% Triton ® X-100, 12 ng/ml of Donor Beads, 12ng/ml of Acceptor Beads Detection incubation overnight, room temperatureFluometer settings Excitation = 680 nM Emission = 570 nM Excitation 680nM Emission = 570 nM Excitation Time = 180 ms Total Measurement Time =550 ms

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) may be demonstrated at IC₅₀ concentrations(concentrations to achieve 50% inhibition) or doses in the range of(0.01 μM to 10 μM).

When tested in the above in-vitro assay the Trk inhibitory activity ofthe following examples was measured at the following IC₅₀s.

Ex IC₅₀ (μM) Example 4 0.020 Example 14 0.022 Example 29 0.015

1. A compound of formula (I):

wherein: R¹ and R² are independently selected from hydrogen, halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁸; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁹;X¹, X² and X³ are independently ═N— or ═CR¹⁰—; R³ and R¹⁰ areindependently selected from hydrogen, halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R¹¹— or heterocyclyl-R¹²—; whereinR³ and R¹⁰ independently of each other may be optionally substituted oncarbon by one or more R¹³; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹⁴; R⁴ is hydrogen or optionally substituted C₁₋₆alkyl;wherein said optional substituents are selected from one or more R¹⁵; R⁵and R⁶ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁵ and R⁶independently of each other may be optionally substituted on carbon byone or more R¹⁶; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁷; A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylenemay be optionally substituted by one or more R¹⁸; Ring C is carbocyclylor heterocyclyl; wherein if said heterocyclyl contains an —NH-moietythat nitrogen may be optionally substituted by a group selected fromR¹⁹; R⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁷ may be optionally substituted on carbon by oneor more R²⁰; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR²¹; n is 0, 1, 2 or 3; wherein the values of R⁷ may be the same ordifferent; R⁸, R¹³, R¹⁵, R¹⁶, R¹⁸ and R²⁰ and are independently selectedfrom halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₁₋₂₋₆alkenyl,C₁₋₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl-R²²— orheterocyclyl-R²³—; wherein R⁸, R¹³, R¹⁵, R¹⁶, R¹⁸ and R²⁰ independentlyof each other may be optionally substituted on carbon by one or moreR²⁴; and wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R²⁵; R⁹,R¹⁴, R¹⁷, R¹⁹, R²¹ and R²⁵ are independently selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁹, R¹⁴, R¹⁷,R¹⁹, R²¹ and R²⁵ independently of each other may be optionallysubstituted on carbon by on or more R²⁶; R²⁴ and R²⁶ are independentlyselected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R²⁴ and R²⁶ independently of each other may beoptionally substituted on carbon by one or more R²⁷; and wherein if saidheterocyclyl contains an —NH-moiety that nitrogen may be optionallysubstituted by a group selected from R²⁸; R¹¹, R¹², R²² and R²³ areindependently selected from a direct bond, —O—, —N(R²⁹)—, —C(O)—,—N(R³⁰)C(O)—, —C(O)N(R³¹)—, —S(O)_(s)—, —SO₂N(R³²)— or —N(R³³)SO₂—;wherein R²⁹, R³⁰, R³¹, R³² and R³³ are independently selected fromhydrogen or C₁₋₆alkyl and s is 0-2; R²⁷ is selected from halo, nitro,cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy,carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and R²⁸ is selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy and carbocyclyl.
 3. A compoundof formula (I) or a pharmaceutically acceptable salt thereof, as claimedin claim 1 wherein R² is hydrogen.
 4. A compound of formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR³ is selected from hydrogen, cyano, carbamoyl, C₁₋₆alkyl andC₁₋₆alkoxycarbonyl; wherein R³ may be optionally substituted on carbonby one or more R¹³; and R¹³ is hydroxy.
 5. A compound of formula (I) ora pharmaceutically acceptable salt thereof, as claimed in claim 1wherein R⁴ is hydrogen.
 6. A compound of formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR⁵ and R⁶ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁵ and R⁶ independently of each other may be optionally substituted oncarbon by one or more R¹⁶; wherein R¹⁶ is hydroxy.
 7. A compound offormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1 wherein A is a direct bond or C₁₋₂alkylene; wherein saidC₁₋₂alkylene may be optionally substituted by one or more R¹⁸; whereinR¹⁸ is hydroxy.
 8. A compound of formula (I) or a pharmaceuticallyacceptable salt thereof, as claimed in claim 1 wherein Ring C is phenyl,pyridyl, 1,3-benzodioxolyl or 1H-indolyl.
 9. A compound of formula (I)or a pharmaceutically acceptable salt thereof, as claimed in claim 1wherein R⁷ is selected from halo and C₁₋₆alkyl; wherein R⁷ may beoptionally substituted on carbon by one or more R²⁰; wherein R²⁰ ishalo.
 10. A compound of formula (I) or a pharmaceutically acceptablesalt thereof, as claimed in claim 1 wherein n is 0, 1 or 2; wherein thevalues of R⁷ may be the same or different.
 11. A compound of formula(I):

wherein: R¹ is selected from methyl, isopropoxy and cyclopropyl; R² ishydrogen; X¹, X² and X³ are independently ═N— or ═CR¹⁰—; R³ is selectedfrom hydrogen, cyano, carbamoyl, methyl, hydroxymethyl andmethoxycarbonyl; R¹⁰ is selected from hydrogen, fluoro, chloro, cyano,carbamoyl, methyl, aminomethyl and acetylaminomethyl; R⁴ is hydrogen; R⁵is selected from hydrogen, methyl, ethyl or hydroxymethyl; R⁶ isselected from hydrogen or hydroxymethyl; A is a direct bond, methyleneor hydroxymethylene; Ring C is phenyl, pyrid-2-yl, 1,3-benzodioxol-5-ylor 1H-indol-3-yl; R⁷ is trifluoromethyl and fluoro; and n is 0, 1 or 2;wherein the values of R⁷ may be the same or different; or apharmaceutically acceptable salt thereof.
 12. A compound of formula (I):

selected from:(2R)-2-[9-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-9H-purin-2-ylamino]-2-(4-fluorophenyl)ethanol;(2R)-2-{[9-(5-cyclopropyl-1H-pyrazol-3-yl)-9H-purin-2-yl]amino}-2-(4-fluorophenyl)ethanol;N—((S)-1-(4-fluorophenyl)ethyl)-9-(5-isopropoxy-1H-pyrazol-3-yl)-9H-purin-2-amine;3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-imidazo[4,5-b]pyridin-5-amine;3-(5-isopropoxy-1H-pyrazol-3-yl)-N—((S)-1-(pyridin-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine;N—((S)-1-(4-fluorophenyl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine;(2R)-2-(4-fluorophenyl)-2-(3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-ylamino)ethanol;6-chloro-N—((S)-1-(4-fluorophenyl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine;3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-benzo[d]imidazol-5-amine;andN-((1-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-yl)methyl)acetamide;or a pharmaceutically acceptable salt thereof
 13. A process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof which process, wherein variable groups are, unlessotherwise specified, as defined in claim 1, wherein said process isselected from: Process a) reaction of a compound of formula (II):

wherein Pg is a nitrogen protecting group; with a compound of formula(III):

wherein L is a displaceable group; Process b) for compounds of formula(I) wherein R⁵ is hydroxymethyl and R⁶ is hydrogen; reaction of acompound of formula (II) with an epoxide of formula (IV):

Process c) for compounds of formula (I) wherein X¹ is ═CR¹⁰—; reacting acompound of formula (V):

with a compound of formula (VI):

Process d) for compounds of formula (I) wherein X¹ is ═N—; reacting acompound of formula (V) with aqueous NaNO₂ solution; Process e) reactinga compound of formula (VII):

wherein L is a displaceable group and Pg is a nitrogen protecting group;with an amine of formula (VIII):

and thereafter if necessary: i) converting a compound of the formula (I)into another compound of the formula (I); ii) removing any protectinggroups; iii) forming a pharmaceutically acceptable salt.
 14. (canceled)15. (canceled)
 16. (canceled)
 17. (canceled)
 18. (canceled)
 19. A methodfor the treatment or prophylaxis of cancer comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim
 1. 20.(canceled)
 21. A pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, as claimedin claim 1, together with at least one pharmaceutically acceptablecarrier, diluent or excipient.
 22. (canceled)
 23. (canceled) 24.(canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)
 28. The methodof use according to claim 19 wherein said cancer is selected fromcongenital fibrosarcoma, mesoblastic nephroma, mesothelioma, acutemyeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma,melanoma, oesophageal cancer, myeloma, hepatocellular, pancreatic,cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi sarcoma, ovariancancer, breast cancer including secretory breast cancer, colorectalcancer, prostate cancer including hormone refractory prostate cancer,bladder cancer, melanoma, lung cancer—non small cell lung cancer(NSCLC), and small cell lung cancer (SCLC), gastric cancer, head andneck cancer, renal cancer, lymphoma, thyroid cancer including papillarythyroid cancer, mesothelioma and leukaemia.